Substrate recognition by the collagen-binding domain of Clostridium histolyticum class I collagenase.
Clostridium histolyticum type I collagenase (ColG) has a segmental structure, S1+S2+S3a+S3b. S3a and S3b bound to insoluble collagen, but S2 did not, thus indicating that S3 forms a collagen-binding domain (CBD). Because S3a+S3b showed the most efficient binding to substrate, cooperative binding by both domains was suggested for the enzyme. Monomeric (S3b) and tandem (S3a+S3b) CBDs bound to atelocollagen, which contains only the collagenous region. However, they did not bind to telopeptides immobilized on Sepharose beads. These results suggested that the binding site(s) for the CBD is(are) present in the collagenous region. The CBD bound to immobilized collagenous peptides, (Pro-Hyp-Gly)(n) and (Pro-Pro-Gly)(n), only when n is large enough to allow the peptides to have a triple-helical conformation. They did not bind to various peptides with similar amino acid sequences or to gelatin, which lacks a triple-helical conformation. The CBD did not bind to immobilized Glc-Gal disaccharide, which is attached to the side chains of hydroxylysine residues in the collagenous region. These observations suggested that the CBD specifically recognizes the triple-helical conformation made by three polypeptide chains in the collagenous region.


PAS-cal: A repetitive peptide sequence calibration standard for MALDI mass spectrometry.
Mass spectrometers equipped with matrix-assisted laser desorption/ionization (MALDI-MS) require frequent multipoint calibration to obtain good mass accuracy over a wide mass range and across large numbers of samples. In this study, we introduce a new synthetic peptide mass calibration standard termed PAS-cal tailored for MALDI-MS based bottom-up proteomics. This standard consists of 30 peptides between 8 and 37 amino acids long and each constructed to contain repetitive sequences of Pro, Ala and Ser as well as one C-terminal arginine residue. MALDI spectra thus cover a mass range between 750 and 3200 m/z in MS mode and between 100 and 3200 m/z in MS/MS mode. Our results show that multipoint calibration of MS spectra using PAS-cal peptides compares well to current commercial reagents for protein identification by PMF. Calibration of tandem mass spectra from LC-MALDI experiments using the longest peptide, PAS-cal37, resulted in smaller fragment ion mass errors, more matching fragment ions and more protein and peptide identifications compared to commercial standards, making the PAS-cal standard generically useful for bottom-up proteomics.


Evaluating the effectiveness of the SMART contract-signing strategy in reducing the growth of Swedish Adolescents' substance use and problem behaviors.
In 2013, around 40 % of the schools in Sweden had structured programs to prevent tobacco and alcohol debut in compulsory school. There has unfortunately been a lack of scientific evidence to support most of the prevention methods focusing on primary prevention in schools in Sweden. The aim and purpose of the present study is to evaluate the effectiveness of the Non-Governmental Organization SMART contract-signing strategy in reducing the growth of youth substance use and other problem behaviors amongst Swedish adolescents. Students from five schools in a medium-sized Swedish municipality were surveyed in three waves from 7(th) to 9(th) grade of compulsory school. We used General Linear Model (GLM) repeated-measures ANOVA to test if the outcome measures smoking, use of snus and alcohol, drunkenness, delinquency, and bullying significantly changed different amounts over time in groups that had participated in the SMART program for long time, a short time, sporadically- or not at all. Groups were compared on demographic background variables, and outcome measures were assessed on all measurement occasions by a one-way ANOVA. The magnitude of group differences at the end of the study was estimated according to Cohen's d. Number of years with a contract has an effect on the levels of self-reported youth problems in 9(th) grade. We found small to medium-sized differences in measured outcomes between students who participated in the program for the longest period of time, 5 years, and who participated for the shortest time, 0-2 years. Findings suggests that the SMART program has preventive effects on adolescent substance use.


Microarray analysis of the transcriptional responses of Clostridium difficile to environmental and antibiotic stress.
Clostridium difficile is a spore-forming anaerobic bacterium that is an emerging nosocomial threat; incidence of infection in hospitals is increasing, both in frequency and severity, resulting in considerable morbidity and mortality. In order to adapt to the intestinal environment, C. difficile must react to the many stresses involved with colonization, including exposure to antibiotics, which represents the most frequent precipitating agent of C. difficile infection. The responses of C. difficile to environmental shocks (heat, pH and oxidative shock) and to growth in the presence of subinhibitory concentrations of antibiotics (amoxicillin, clindamycin and metronidazole) were investigated using the C. difficile 630 microarray developed by the Bacterial Microarray Group at St George's, University of London, UK (BmuG@S). Significantly regulated genes and operons were identified that are unique to or common between different stresses. The transcriptional profiles of C. difficile 630 are similar after growth in the presence of amoxicillin and clindamycin: both increased transcription of ribosomal protein genes and altered transcription of genes encoding surface-associated proteins. In contrast, metronidazole treatment resulted in minor changes in transcription patterns. The general stress response is observed after heat shock and acid shock. Heat shock also affected transcription of several biochemical pathways. Exposure to atmospheric oxygen induced a large number of electron transporters. This study provides a starting point for detailed analyses of numerous genes whose expression is affected by stress and may therefore be involved in adaptation to the host environment.


Reactivity control of a photocatalytic system by changing the light intensity.
We report a novel light-intensity dependent reactivity approach allowing us to selectively switch between triplet energy transfer and electron transfer reactions, or to regulate the redox potential available for challenging reductions. Simply by adjusting the light power density with an inexpensive lens while keeping all other parameters constant, we achieved control over one- and two-photon mechanisms, and successfully exploited our approach for lab-scale photoreactions using three substrate classes with excellent selectivities and good product yields. Specifically, our proof-of-concept study demonstrates that the irradiation intensity can be used to control (i) the available photoredox reactivity for reductive dehalogenations to selectively target either bromo- or chloro-substituted arenes, (ii) the photochemical cis-trans isomerization of olefins versus their photoreduction, and (iii) the competition between hydrogen atom abstraction and radical dimerization processes.


Metabolic activity of the basal ganglia in parkinsonian syndromes in human and non-human primates: a cytochrome oxidase histochemistry study.
In order to examine the consequences of nigrostriatal denervation on metabolic and functional activity of the basal ganglia, we analysed the distribution of cytochrome oxidase, a metabolic marker for neuronal functional activity, throughout the different basal ganglia structures in parkinsonian syndromes. The study was performed using enzyme histochemistry and densitometric measurements in patients with Parkinson's disease and in monkeys rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrydine (MPTP) intoxication. In MPTP-intoxicated monkeys compared to control animals, enzyme activity was significantly increased in the subthalamic nucleus and in the output nuclei of the basal ganglia, e.g. the internal segment of the globus pallidus and the substantia nigra pars reticulata, but remained unchanged in the external segment of the globus pallidus and the striatum. L-DOPA treatment reversed the increased enzyme activity in all of the affected structures studied. In contrast, in parkinsonian patients, who had all been chronically treated with L-DOPA, no changes in enzyme activity were detected compared to control subjects. The results in MPTP-intoxicated monkeys are in agreement with the accepted model of basal ganglia organization, in which the output nuclei of the basal ganglia are considered to be overactive after nigrostriatal denervation, partly due to increased activity of excitatory afferents from the subthalamic nucleus. Since the increased enzyme activity in MPTP-intoxicated monkeys was reversed by L-DOPA therapy, the unchanged cytochrome oxidase activity observed in parkinsonian patients might result from L-DOPA treatment, combined with the chronicity of nigrostriatal denervation.


Twenty years of the Italian Fanconi Anemia Registry: where we stand and what remains to be learned.
The natural history of Fanconi anemia remains hard to establish because of its rarity and its heterogeneous clinical presentation; since 1994, the Italian Fanconi Anemia Registry has collected clinical, epidemiological and genetic data of Italian Fanconi Anemia patients. This registry includes 180 patients with a confirmed diagnosis of Fanconi anemia who have either been enrolled prospectively, at diagnosis, or later on. After enrollment, follow-up data were periodically collected to assess the clinical course, possible complications and long-term survival; the median follow up was 15.6 years. The main goal of the study was to describe the natural history of Fanconi anemia, focusing on the following variables: family history, disease presentation, development of hematological manifestations, development of malignancies, occurrence of hematopoietic stem cell transplantation and survival. Typical morphological and/or hematological abnormalities and/or growth retardation were the most common manifestations at diagnosis; the majority of patients (77%) exhibited hematological abnormalities at the initial presentation, and almost all (96%) eventually developed hematological manifestations. More than half of the patients (57%) underwent a bone-marrow transplant. The occurrence of cancer was quite rare at diagnosis, whereas the cumulative incidence of malignancies at 10, 20 and 30 years was 5%, 8% and 22%, respectively, for hematological cancers and 1%, 15% and 32%, respectively, for solid tumors. Overall survival at 10, 20 and 30 years were 88%, 56% and 37%, respectively; the main causes of death were cancer, complications of the hematological presentation and complications of transplantation. These data clearly confirm the detrimental outcome of Fanconi anemia, with no major improvement in the past decades.


Looking forward to the next 15 years: innovation and new pathways for research in health equity.
Since our launch in 2002, the International Journal for Equity in Health (IJEqH) has furthered our collective understanding of equity in health and health services by providing a platform on which academics and practitioners can share their work. Today, we celebrate our fifteenth anniversary with an article collection that presents a call for new and novel research in equity in health and we invite our authors to use new approaches and methods, and to focus on emerging areas of research related to health equity in order to set the stage for the next fifteen years of health equity research.Our anniversary issue provides a platform for expanding the conceptualization, diversity of populations and study designs, and for increasing the use of novel methodologies in the field. The IJEqH has helped to support the wider group of researchers, policymakers and practitioners with a commitment to social justice and equity but there is still more to do. With the help of the highly committed editorial team and editorial board, the innovative work of researchers worldwide, and the countless of hours dedicated by hundreds of reviewers, we are confident in the IJEqH's ability to continue supporting the dissemination of health equity research for years to come.


Quality-assured measurements of animal building emissions: particulate matter concentrations.
Federally funded, multistate field studies were initiated in 2002 to measure emissions of particulate matter (PM) < 10 microm (PM10) and total suspended particulate (TSP), ammonia, hydrogen sulfide, carbon dioxide, methane, nonmethane hydrocarbons, and odor from swine and poultry production buildings in the United States. This paper describes the use of a continuous PM analyzer based on the tapered element oscillating microbalance (TEOM). In these studies, the TEOM was used to measure PM emissions at identical locations in paired barns. Measuring PM concentrations in swine and poultry barns, compared with measuring PM in ambient air, required more frequent maintenance of the TEOM. External screens were used to prevent rapid plugging of the insect screen in the PM10 preseparator inlet. Minute means of mass concentrations exhibited a sinusoidal pattern that followed the variation of relative humidity, indicating that mass concentration measurements were affected by water vapor condensation onto and evaporation of moisture from the TEOM filter. Filter loading increased the humidity effect, most likely because of increased water vapor adsorption capacity of added PM. In a single layer barn study, collocated TEOMs, equipped with TSP and PM10 inlets, corresponded well when placed near the inlets of exhaust fans in a layer barn. Initial data showed that average daily mean concentrations of TSP, PM10, and PM2.5 concentrations at a layer barn were 1440 +/- 182 microg/m3 (n = 2), 553 +/- 79 microg/m3 (n = 4), and 33 +/- 75 microg/m3 (n = 1), respectively. The daily mean TSP concentration (n = 1) of a swine barn sprinkled with soybean oil was 67% lower than an untreated swine barn, which had a daily mean TSP concentration of 1143 +/- 619 microg/m3. The daily mean ambient TSP concentration (n = 1) near the swine barns was 25 +/- 8 microg/m3. Concentrations of PM inside the swine barns were correlated to pig activity.


Linkage of osteoporosis to chromosome 20p12 and association to BMP2.
Osteoporotic fractures are a major cause of morbidity and mortality in ageing populations. Osteoporosis, defined as low bone mineral density (BMD) and associated fractures, have significant genetic components that are largely unknown. Linkage analysis in a large number of extended osteoporosis families in Iceland, using a phenotype that combines osteoporotic fractures and BMD measurements, showed linkage to Chromosome 20p12.3 (multipoint allele-sharing LOD, 5.10; p value, 6.3 x 10(-7)), results that are statistically significant after adjusting for the number of phenotypes tested and the genome-wide search. A follow-up association analysis using closely spaced polymorphic markers was performed. Three variants in the bone morphogenetic protein 2 (BMP2) gene, a missense polymorphism and two anonymous single nucleotide polymorphism haplotypes, were determined to be associated with osteoporosis in the Icelandic patients. The association is seen with many definitions of an osteoporotic phenotype, including osteoporotic fractures as well as low BMD, both before and after menopause. A replication study with a Danish cohort of postmenopausal women was conducted to confirm the contribution of the three identified variants. In conclusion, we find that a region on the short arm of Chromosome 20 contains a gene or genes that appear to be a major risk factor for osteoporosis and osteoporotic fractures, and our evidence supports the view that BMP2 is at least one of these genes.


Intravascular delivery of particulate systems: does geometry really matter?
In cancer therapy and imaging, the systemic passive delivery of particulate systems has relied on the enhanced permeability and retention (EPR) effect: sufficiently small particles can cross the endothelial fenestrations and accumulate in the tumor parenchyma. The vast majority of man-made particulates exhibit a spherical shape as a result of surface energy minimization during their synthesis. The advent of phage display libraries, which are revealing the extraordinary molecular diversity of endothelial cells, and the development of processes for fabricating particles with shapes other than spherical are opening the path to new design solutions for systemically administered targeted particulates. In this paper, the role of particle geometry (i.e., size and shape) is discussed at the tissue and cellular scales. Emphasis is placed on how the synergistic effect of particle geometry and molecular targeting can enhance the specificity of delivery. The intravascular delivery process has been broken into three events: margination, firm adhesion and control of internalization. Predictions from mathematical models and observations from in-vitro experiments were used to show the relevance of particle geometry in systemic delivery. Rational design of particulate systems should consider, beside the physico-chemical properties of the surface coatings, geometrical features as size and shape. The integration of mathematical modeling with in-vitro and in-vivo testing provides the tools for establishing a rational design of nanoparticles.


Analysis and Visualization of ChIP-Seq and RNA-Seq Sequence Alignments Using ngs.plot.
The continual maturation and increasing applications of next-generation sequencing technology in scientific research have yielded ever-increasing amounts of data that need to be effectively and efficiently analyzed and innovatively mined for new biological insights. We have developed ngs.plot-a quick and easy-to-use bioinformatics tool that performs visualizations of the spatial relationships between sequencing alignment enrichment and specific genomic features or regions. More importantly, ngs.plot is customizable beyond the use of standard genomic feature databases to allow the analysis and visualization of user-specified regions of interest generated by the user's own hypotheses. In this protocol, we demonstrate and explain the use of ngs.plot using command line executions, as well as a web-based workflow on the Galaxy framework. We replicate the underlying commands used in the analysis of a true biological dataset that we had reported and published earlier and demonstrate how ngs.plot can easily generate publication-ready figures. With ngs.plot, users would be able to efficiently and innovatively mine their own datasets without having to be involved in the technical aspects of sequence coverage calculations and genomic databases.


Ectopic, submandibular thyroid causing hyperthyroidism.
Ectopic thyroid tissue in the submandibular region is exceptionally rare. Nevertheless, the treating physician should consider this condition within the differential diagnosis of a submandibular mass. Case report of ectopic thyroid tissue presenting as a submandibular mass in a patient with hyperthyroidism, together with a review of the English-literature concerning ectopic thyroid tissue. To our knowledge, this is the first report of ectopic thyroid tissue presenting as a submandibular mass and causing hyperthyroidism. Removal of the submandibular mass resulted in normalisation of thyroid function, and subsequent reduction in the patient's antithyroid medication dosage. Ectopic thyroid tissue should be suspected in any patient with a submandibular mass. Prior to resection of such a lesion, it is essential to ensure that normal, functioning thyroid tissue is present elsewhere. Ectopic thyroid tissue can also present with pathology similar to that affecting the normal thyroid gland.


Two-dimensional nanochannel membranes for molecular and ionic separations.
Two-dimensional (2D) nanosheets have emerged as promising functional materials owing to their atomic thickness and unique physical/chemical properties. By using 2D nanosheets as building blocks, diverse kinds of two-dimensional nanochannel membranes (2DNCMs) are being actively explored, in which mass transport occurs in the through-plane and interlayer channels of 2D nanosheets. The rational construction and physical/chemical microenvironment regulation of nanochannels are of vital significance for translating these 2D nanosheets into molecular separation membranes and ionic separation membranes. Focusing on the recent advances of 2DNCMs, in this review, various porous/nonporous 2D nanosheets and their derived nanochannels are first briefly introduced. Then we discuss the emerging top-down and bottom-up methods to synthesize high-quality 2D nanosheets and to prepare high-performance 2DNCMs. As the major part of this review, we focus on three types of nanochannels, which are based on nonporous nanosheets, intrinsically porous nanosheets and perforated nanosheets. The strategies for regulating the physical and chemical microenvironments in the nanochannels are emphasized. The representative applications of 2DNCMs in molecular separations (gas separation, liquid separation) and ionic separations are presented. Finally, the current challenges and future perspectives are highlighted.


Charge displacements during ATP-hydrolysis and synthesis of the Na+-transporting FoF1-ATPase of Ilyobacter tartaricus.
Transient electrical currents generated by the Na(+)-transporting F(o)F(1)-ATPase of Ilyobacter tartaricus were observed in the hydrolytic and synthetic mode of the enzyme. Two techniques were applied: a photochemical ATP concentration jump on a planar lipid membrane and a rapid solution exchange on a solid supported membrane. We have identified an electrogenic reaction in the reaction cycle of the F(o)F(1)-ATPase that is related to the translocation of the cation through the membrane bound F(o) subcomplex of the ATPase. In addition, we have determined rate constants for the process: For ATP hydrolysis this reaction has a rate constant of 15-30 s(-1) if H(+) is transported and 30-60 s(-1) if Na(+) is transported. For ATP synthesis the rate constant is 50-70 s(-1).


Oral administration of 3,3'-diindolylmethane inhibits lung metastasis of 4T1 murine mammary carcinoma cells in BALB/c mice.
3,3'-diindolylmethane (DIM) is the major in vivo product of the acid-catalyzed oligomerization of indole-3-carbinol present in cruciferous vegetables, and it has been shown to exhibit anticancer properties. In this study, we assessed the effects of DIM on the metastasis of 4T1 mouse mammary carcinoma cells. In vitro culture studies showed that DIM dose-dependently inhibited the migration, invasion, and adhesion of 4T1 cells at concentrations of 0-10 micromol/L without attendant changes in cell viability. In an in vivo lung metastasis model, 4T1 cells (2 x 10(5) cells/mouse) were injected into the tail veins of syngeneic female BALB/c mice. Beginning on the second day, the mice were subjected to gavage with 0-10 mg DIM/(kg body weight x d) for 13 d. Oral DIM administration resulted in a marked reduction in the number of pulmonary tumor nodules. DIM treatment significantly reduced the levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, and vascular cell adhesion molecule (VCAM)-1 and increased TIMP-2 levels in the sera and lungs of mice injected with 4T1 cells. Additionally, DIM treatment reduced the serum concentrations of interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)alpha. We have demonstrated that DIM profoundly inhibits the lung metastasis of 4T1 cells, which was accompanied by reduced levels of MMP, adhesion molecules, and proinflammatory cytokines. These results indicate that DIM has potential as an antimetastatic agent for the treatment of breast cancer.


Sparse Multiview Task-Centralized Ensemble Learning for ASD Diagnosis Based on Age- and Sex-Related Functional Connectivity Patterns.
Autism spectrum disorder (ASD) is an age- and sex-related neurodevelopmental disorder that alters the brain's functional connectivity (FC). The changes caused by ASD are associated with different age- and sex-related patterns in neuroimaging data. However, most contemporary computer-assisted ASD diagnosis methods ignore the aforementioned age-/sex-related patterns. In this paper, we propose a novel sparse multiview task-centralized (Sparse-MVTC) ensemble classification method for image-based ASD diagnosis. Specifically, with the age and sex information of each subject, we formulate the classification as a multitask learning problem, where each task corresponds to learning upon a specific age/sex group. We also extract multiview features per subject to better reveal the FC changes. Then, in Sparse-MVTC learning, we select a certain central task and treat the rest as auxiliary tasks. By considering both task-task and view-view relationships between the central task and each auxiliary task, we can learn better upon the entire dataset. Finally, by selecting the central task, in turn, we are able to derive multiple classifiers for each task/group. An ensemble strategy is further adopted, such that the final diagnosis can be integrated for each subject. Our comprehensive experiments on the ABIDE database demonstrate that our proposed Sparse-MVTC ensemble learning can significantly outperform the state-of-the-art classification methods for ASD diagnosis.


Mangrove expansion and salt marsh decline at mangrove poleward limits.
Mangroves are species of halophytic intertidal trees and shrubs derived from tropical genera and are likely delimited in latitudinal range by varying sensitivity to cold. There is now sufficient evidence that mangrove species have proliferated at or near their poleward limits on at least five continents over the past half century, at the expense of salt marsh. Avicennia is the most cold-tolerant genus worldwide, and is the subject of most of the observed changes. Avicennia germinans has extended in range along the USA Atlantic coast and expanded into salt marsh as a consequence of lower frost frequency and intensity in the southern USA. The genus has also expanded into salt marsh at its southern limit in Peru, and on the Pacific coast of Mexico. Mangroves of several species have expanded in extent and replaced salt marsh where protected within mangrove reserves in Guangdong Province, China. In south-eastern Australia, the expansion of Avicennia marina into salt marshes is now well documented, and Rhizophora stylosa has extended its range southward, while showing strong population growth within estuaries along its southern limits in northern New South Wales. Avicennia marina has extended its range southwards in South Africa. The changes are consistent with the poleward extension of temperature thresholds coincident with sea-level rise, although the specific mechanism of range extension might be complicated by limitations on dispersal or other factors. The shift from salt marsh to mangrove dominance on subtropical and temperate shorelines has important implications for ecological structure, function, and global change adaptation.


Subjective well-being and month-long LF/HF ratio among deskworkers.
The importance of workers' well-being has been recognized in recent years. The assessment of well-being has been subjective, and few studies have sought potential biomarkers of well-being to date. This study examined the relationship between well-being and the LF/HF ratio, an index of heart rate variability that reflects sympathetic and parasympathetic nerve activity. Pulse waves were measured using photoplethysmography through a web camera attached to the computer used by each participant. The participants were asked to measure their pulse waves while working for 4 weeks, and well-being was assessed using self-reported measures such as the Satisfaction With Life Scale (SWLS), the Positive and Negative Affect Schedule (PANAS), and the Flourishing Scale (FS). Each of the well-being scores were split into two groups according to the median value, and the LF/HF ratio during work, as well as the number of times an LF/HF ratio threshold was either exceeded or subceeded, were compared between the high and low SWLS, positive emotion, negative emotion, and FS groups. Furthermore, to examine the effects of the LF/HF ratio and demographic characteristics on well-being, a multiple regression analysis was conducted. Data were obtained from 169 participants. The results showed that the low FS group had a higher mean LF/HF ratio during work than the high FS group. No significant differences were seen between the high and low SWLS groups, the high and low positive emotion groups, or the high and low negative emotion groups. The multiple regression analysis showed that the mean LF/HF ratio during work affected the FS and SWLS scores, and the number of times the mean LF/HF ratio exceeded +3 SD had an effect on the positive emotion. No effect of the LF/HF ratio on negative emotions was shown. The LF/HF ratio might be applicable as an objective measure of well-being.


Farming Systems and Rural Out-Migration in Nang Rong, Thailand and Chitwan Valley, Nepal.
Using data from two post-frontier rural settings, Nang Rong, Thailand (N=2,538) and Chitwan Valley, Nepal (N=876), this paper examines agricultural push factors determining the outmigration of young people age 15 to 19. We focus on different dimensions of migration, including distance and duration. Our study examines a wide array of agricultural determinants, each with its own potential effect on migration. These determinants include land tenure, crop portfolios, animal husbandry activities, and use of farm inputs. We link these proximal causes to two underlying mechanisms: risk and amenities. We examine these determinants using separate models across settings. Our results indicate that agricultural factors are significant determinants of migration in both contexts. However, different factors operate in different settings, indicating the importance of contextual variation in explaining the manner in which risks and amenities influence agricultural determinants of migration.


Histopathological features of epithelioid malignant pleural mesotheliomas in patients with extended survival.
Diffuse malignant mesothelioma (DMM) of the pleura is a rare and aggressive disease, wherein the long-term survival (LTS) rate is low. The epithelioid subtype is the most prevalent form of DMM with the best prognosis. To study prognostic histopathologic factors associated with extended survival in epithelioid DMM, we examined 43 tumors from patients with survival more than five years (LTSs) and compared the findings with 84 tumors from a reference group (RG) with average survival. We analyzed the tumors considering previously published histopathological prognostic features and attempted to identify additional morphological features predictive of extended survival. Most of the LTS tumors presented with nuclear grade I (n = 34, 90%) and a tubulopapillary growth pattern (n = 30, 70%). One LTS tumor had necrosis. In contrast, nuclear grade II (n = 49, 61%) and solid growth pattern (n = 59, 70%) were more frequent in the RG, and necrosis was present in 16 (19%) tumors. We also evaluated the association of asbestos lung tissue fiber burden quantified from autopsy samples with histopathological features and found that elevated asbestos fiber was associated with higher nuclear grade (P < 0.001) and the presence of necrosis (P = 0.021). In univariate survival analysis, we identified the following three novel morphological features associated with survival: exophytic polypoid growth pattern, tumor density, and single mesothelium layered tubular structures. After adjustments, low nuclear grade (P < 0.001) and presence of exophytic polypoid growth (P = 0.024) were associated with prolonged survival. These results may aid in estimating DMM prognosis.


Gut/brain axis and the microbiota.
Tremendous progress has been made in characterizing the bidirectional interactions between the central nervous system, the enteric nervous system, and the gastrointestinal tract. A series of provocative preclinical studies have suggested a prominent role for the gut microbiota in these gut-brain interactions. Based on studies using rodents raised in a germ-free environment, the gut microbiota appears to influence the development of emotional behavior, stress- and pain-modulation systems, and brain neurotransmitter systems. Additionally, microbiota perturbations by probiotics and antibiotics exert modulatory effects on some of these measures in adult animals. Current evidence suggests that multiple mechanisms, including endocrine and neurocrine pathways, may be involved in gut microbiota-to-brain signaling and that the brain can in turn alter microbial composition and behavior via the autonomic nervous system. Limited information is available on how these findings may translate to healthy humans or to disease states involving the brain or the gut/brain axis. Future research needs to focus on confirming that the rodent findings are translatable to human physiology and to diseases such as irritable bowel syndrome, autism, anxiety, depression, and Parkinson's disease.


Trans-saccadic processing of visual and motor planning during sequential eye movements.
How the brain maintains perceptual continuity across eye movements that yield discontinuous snapshots of the world is still poorly understood. In this study, we adapted a framework from the dual-task paradigm, well suited to reveal bottlenecks in mental processing, to study how information is processed across sequential saccades. The pattern of RTs allowed us to distinguish among three forms of trans-saccadic processing (no trans-saccadic processing, trans-saccadic visual processing and trans-saccadic visual processing and saccade planning models). Using a cued double-step saccade task, we show that even though saccade execution is a processing bottleneck, limiting access to incoming visual information, partial visual and motor processing that occur prior to saccade execution is used to guide the next eye movement. These results provide insights into how the oculomotor system is designed to process information across multiple fixations that occur during natural scanning.


Characterization of the gene encoding nitrite reductase and the physiological consequences of its expression in the nondenitrifying Rhizobium "hedysari" strain HCNT1.
Rhizobium "hedysari" HCNT1 is an unclassified rhizobium which contains a nitric oxide-producing nitrite reductase but is apparently incapable of coupling the reduction of nitrite to energy conservation. The gene encoding the nitrite reductase, nirK, has been cloned and sequenced and was found to encode a protein closely related to the copper-containing family of nitrite reductases. Unlike other members of this family, nirK expression in HCNT1 is not dependent on the presence of nitrogen oxides, being dependent only on oxygen concentration. Oxygen respiration of microaerobically grown Nir-deficient cells is not affected by concentrations of nitrite that completely inhibit oxygen respiration in wild-type cells. This loss of sensitivity suggests that the product of nitrite reductase, nitric oxide, is responsible for inhibition of oxygen respiration. By using a newly developed chemically modified electrode to detect nitric oxide, it was found that nitrite reduction by HCNT1 produces significantly higher nitric oxide concentrations than are observed in true denitrifiers. This indicates that nitrite reductase is the only nitrogen oxide reductase active in HCNT1. The capacity to generate such large concentrations of freely diffusible nitric oxide as a consequence of nitrite respiration makes HCNT1 unique among bacteria.


Implicit processing of phonotactic cues: evidence from electrophysiological and vascular responses.
Spoken word recognition is achieved via competition between activated lexical candidates that match the incoming speech input. The competition is modulated by prelexical cues that are important for segmenting the auditory speech stream into linguistic units. One such prelexical cue that listeners rely on in spoken word recognition is phonotactics. Phonotactics defines possible combinations of phonemes within syllables or words in a given language. The present study aimed at investigating both temporal and topographical aspects of the neuronal correlates of phonotactic processing by simultaneously applying ERPs and functional near-infrared spectroscopy (fNIRS). Pseudowords, either phonotactically legal or illegal with respect to the participants' native language, were acoustically presented to passively listening adult native German speakers. ERPs showed a larger N400 effect for phonotactically legal compared to illegal pseudowords, suggesting stronger lexical activation mechanisms in phonotactically legal material. fNIRS revealed a left hemispheric network including fronto-temporal regions with greater response to phonotactically legal pseudowords than to illegal pseudowords. This confirms earlier hypotheses on a left hemispheric dominance of phonotactic processing most likely due to the fact that phonotactics is related to phonological processing and represents a segmental feature of language comprehension. These segmental linguistic properties of a stimulus are predominantly processed in the left hemisphere. Thus, our study provides first insights into temporal and topographical characteristics of phonotactic processing mechanisms in a passive listening task. Differential brain responses between known and unknown phonotactic rules thus supply evidence for an implicit use of phonotactic cues to guide lexical activation mechanisms.


Blocking eIF5A modification in cervical cancer cells alters the expression of cancer-related genes and suppresses cell proliferation.
Cancer etiology is influenced by alterations in protein synthesis that are not fully understood. In this study, we took a novel approach to investigate the role of the eukaryotic translation initiation factor eIF5A in human cervical cancers, where it is widely overexpressed. eIF5A contains the distinctive amino acid hypusine, which is formed by a posttranslational modification event requiring deoxyhypusine hydroxylase (DOHH), an enzyme that can be inhibited by the drugs ciclopirox and deferiprone. We found that proliferation of cervical cancer cells can be blocked by DOHH inhibition with either of these pharmacologic agents, as well as by RNA interference-mediated silencing of eIF5A, DOHH, or another enzyme in the hypusine pathway. Proteomic and RNA analyses in HeLa cervical cancer cells identified two groups of proteins in addition to eIF5A that were coordinately affected by ciclopirox and deferiprone. Group 1 proteins (Hsp27, NM23, and DJ-1) were downregulated at the translational level, whereas group 2 proteins (TrpRS and PRDX2) were upregulated at the mRNA level. Further investigations confirmed that eIF5A and DOHH are required for Hsp27 expression in cervical cancer cells and for regulation of its key target IκB and hence NF-κB. Our results argue that mature eIF5A controls a translational network of cancer-driving genes, termed the eIF5A regulon, at the levels of mRNA abundance and translation. In coordinating cell proliferation, the eIF5A regulon can be modulated by drugs such as ciclopirox or deferiprone, which might be repositioned to control cancer cell growth.


Probing charge transfer characteristics in a donor-acceptor metal-organic framework by Raman spectroelectrochemistry and pressure-dependence studies.
The stimuli responsive behaviour of charge transfer donor-acceptor metal-organic frameworks (MOFs) remains an understudied phenomenon which may have applications in tuneable electronic materials. We now report the modification of donor-acceptor charge transfer characteristics in a semiconducting tetrathiafulvalene-naphthalene diimide-based MOF under applied electrochemical bias and pressure. We employ a facile solid state in situ Raman spectroelectrochemical technique, applied for the first time in the characterisation of electroactive MOFs, to monitor the formation of a new complex TTFTC˙+-DPNI from a largely neutral system, upon electrochemical oxidation of the framework. In situ pressure-dependent Raman spectroscopy and powder X-ray diffraction experiments performed in a diamond anvil cell revealed blue shifts in the donor and acceptor vibrational modes in addition to contractions in the unit cell which are indicative of bond shortening. This study demonstrates the utility of in situ Raman spectroscopic techniques in the characterisation of redox-active MOFs and the elucidation of their electronic behaviours.


Therapeutic effects of honokiol on motor impairment in hemiparkinsonian mice are associated with reversing neurodegeneration and targeting PPARγ regulation.
Parkinson's disease (PD) is a profound neurodegenerative disorder with gradual loss of dopamine nigrostriatal neurons linked to serious behavioral symptoms. While the current treatment strategies present limitations on halting the progression of PD, this study aimed to investigate the therapeutic potential of honokiol, as a partial peroxisome proliferator-activated receptor-gamma (PPARγ) mimic, on the proceeding behavioral and biochemical alterations in hemiparkinsonian mice. Results showed that unilateral striatal 6-hydroxydopamine (6-OHDA)-lesioned mice exhibited motor impairment, reflecting the contralateral rotation induced by apomorphine at 1-3 weeks post-lesion. Subchronic honokiol administration for 1-2 weeks, beginning 7 days after 6-OHDA-lesion, dose-dependently ameliorated motor dysfunction in hemiparkinsonian mice. Recovery of motor function was correlated with reversal of nigrostriatal dopaminergic neuronal loss, accompanied by higher tyrosine hydroxylase (TH) density, dopamine transporter (DAT) expression and vesicular monoamine transporter-2 (VMAT2) levels. Furthermore, honokiol attenuated oxidative stress and reactive astrocyte induction via decreasing NADPH-oxidase and glial fibrillary acidic protein (GFAP) expressions in 6-OHDA-lesioned striatum. The reversal effects of honokiol on behavioral impairment and striatal PPARγ expression were impeded by PPARγ antagonist GW9662. Notably, subchronic honokiol treatment extended the lifespan of these hemiparkinsonian mice. The present findings demonstrate the therapeutic activities of honokiol in ameliorating motor impairment and progressive dopaminergic damage that could be associated with regulating PPARγ signaling. Therefore, honokiol may potentially exert as a novel therapeutic candidate through PPARγ activation for management of motor symptoms and progressive neurodegeneration in PD.


Democrats and republicans can be differentiated from their faces.
Individuals' faces communicate a great deal of information about them. Although some of this information tends to be perceptually obvious (such as race and sex), much of it is perceptually ambiguous, without clear or obvious visual cues. Here we found that individuals' political affiliations could be accurately discerned from their faces. In Study 1, perceivers were able to accurately distinguish whether U.S. Senate candidates were either Democrats or Republicans based on photos of their faces. Study 2 showed that these effects extended to Democrat and Republican college students, based on their senior yearbook photos. Study 3 then showed that these judgments were related to differences in perceived traits among the Democrat and Republican faces. Republicans were perceived as more powerful than Democrats. Moreover, as individual targets were perceived to be more powerful, they were more likely to be perceived as Republicans by others. Similarly, as individual targets were perceived to be warmer, they were more likely to be perceived as Democrats. These data suggest that perceivers' beliefs about who is a Democrat and Republican may be based on perceptions of traits stereotypically associated with the two political parties and that, indeed, the guidance of these stereotypes may lead to categorizations of others' political affiliations at rates significantly more accurate than chance guessing.


Tailoring of Novel Azithromycin-Loaded Zinc Oxide Nanoparticles for Wound Healing.
Skin is the largest mechanical barrier against invading pathogens. Following skin injury, the healing process immediately starts to regenerate the damaged tissues and to avoid complications that usually include colonization by pathogenic bacteria, leading to fever and sepsis, which further impairs and complicates the healing process. So, there is an urgent need to develop a novel pharmaceutical material that promotes the healing of infected wounds. The present work aimed to prepare and evaluate the efficacy of novel azithromycin-loaded zinc oxide nanoparticles (AZM-ZnONPs) in the treatment of infected wounds. The Box-Behnken design and response surface methodology were used to evaluate loading efficiency and release characteristics of the prepared NPs. The minimum inhibitory concentration (MIC) of the formulations was determined against Staphylococcus aureus and Escherichia coli. Moreover, the anti-bacterial and wound-healing activities of the AZM-loaded ZnONPs impregnated into hydroxyl propyl methylcellulose (HPMC) gel were evaluated in an excisional wound model in rats. The prepared ZnONPs were loaded with AZM by adsorption. The prepared ZnONPs were fully characterized by XRD, EDAX, SEM, TEM, and FT-IR analysis. Particle size distribution for the prepared ZnO and AZM-ZnONPs were determined and found to be 34 and 39 nm, respectively. The mechanism by which AZM adsorbed on the surface of ZnONPs was the best fit by the Freundlich model with a maximum load capacity of 160.4 mg/g. Anti-microbial studies showed that AZM-ZnONPs were more effective than other controls. Using an experimental infection model in rats, AZM-ZnONPs impregnated into HPMC gel enhanced bacterial clearance and epidermal regeneration, and stimulated tissue formation. In conclusion, AZM -loaded ZnONPs are a promising platform for effective and rapid healing of infected wounds.


Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with intermediate and advanced/relapsed hepatocellular carcinoma: a TOS-ESMO initiative endorsed by CSCO, ISMPO, JSMO, KSMO, MOS and SSO.
The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of hepatocellular carcinoma (HCC) was published in 2018, and covered the diagnosis, management, treatment and follow-up of early, intermediate and advanced disease. At the ESMO Asia Meeting in November 2018 it was decided by both the ESMO and the Taiwan Oncology Society (TOS) to convene a special guidelines meeting immediately after the Taiwan Joint Cancer Conference (TJCC) in May 2019 in Taipei. The aim was to adapt the ESMO 2018 guidelines to take into account both the ethnic and the geographic differences in practice associated with the treatment of HCC in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with intermediate and advanced/relapsed HCC representing the oncology societies of Taiwan (TOS), China (CSCO), India (ISMPO) Japan (JSMO), Korea (KSMO), Malaysia (MOS) and Singapore (SSO). The voting was based on scientific evidence, and was independent of the current treatment practices, the drug availability and reimbursement situations in the individual participating Asian countries.


Sex steroid hormones in pairs of tumor and serum from breast cancer patients and pathobiological role of androstene-3β, 17β-diol.
Estrogens play an important role in the pathobiology of breast cancer. In postmenopausal women, peripheral synthesis of estrogens from adrenal/ovarian androgens, dehydroepiandrosterone (DHEA) or androstenedione (Adione), by estrogen-metabolizing enzymes is important. Besides estrone (E1) and estradiol (E2), androgen metabolites, such as androstene-3β, 17β-diol (Aenediol) or 5α-androstane-3β, 17β-diol (Aanediol), are known to have estrogenic functions, although they have been studied much less in breast cancer. To precisely elucidate steroid metabolism in breast cancer patients and to identify the pathobiological role of estrogenic androgen metabolites, concentrations of DHEA, Adione, Aenediol, Aanediol, E1, and E2 in pairs of serum and tumor tissue from patients with primary breast cancer were measured by liquid chromatography-tandem mass spectrometry. Cell proliferation assays using Aenediol were performed for four breast cancer cell lines. Serous E2 concentration was extremely low in postmenopausal women; however, a marked increase in tumor tissue was observed in hormone receptor-positive cases. E1 concentration, in contrast, was sustained at a higher level, even in postmenopausal serum, and did not increase in tumor tissue irrespective of the hormone receptor status. Dehydroepiandrosterone was most abundant in all samples, and exhibited a similar pattern as Adione and Aenediol. 5α-Androstane-3β, 17β-diol was undetectable in most samples. Androstene-3β, 17β-diol proliferated estrogen receptor-apositive breast cancer cells in the absence of E2. The intratumoral increase of E2, but not E1, in hormone receptor-positive postmenopausal breast cancer tissue, as well as the proliferative role of Aenediol, was elucidated.


Exploring mechanisms of fatigue during repeated exercise and the dose dependent effects of carbohydrate and protein ingestion: study protocol for a randomised controlled trial.
Muscle glycogen has been well established as the primary metabolic energy substrate during physical exercise of moderate- to high-intensity and has accordingly been implicated as a limiting factor when such activity is sustained for a prolonged duration. However, the role of this substrate during repeated exercise after limited recovery is less clear, with ongoing debate regarding how recovery processes can best be supported via nutritional intervention. The aim of this project is to examine the causes of fatigue during repeated exercise bouts via manipulation of glycogen availability through nutritional intervention, thus simultaneously informing aspects of the optimal feeding strategy for recovery from prolonged exercise. The project involves two phases with each involving two treatment arms administered in a repeated measures design. For each treatment, participants will be required to exercise to the point of volitional exhaustion on a motorised treadmill at 70% of previously determined maximal oxygen uptake, before a four hour recovery period in which participants will be prescribed solutions providing 1.2 grams of sucrose per kilogram of body mass per hour of recovery (g.kg-1.h-1) relative to either a lower rate of sucrose ingestion (that is, 0.3 g.kg-1. h-1; Phase I) or a moderate dose (that is, 0.8 g.kg-1.h-1) rendered isocaloric via the addition of 0.4 g.kg-1.h-1 whey protein hydrolysate (Phase II); the latter administered in a double blind manner as part of a randomised and counterbalanced design. Muscle biopsies will be sampled at the beginning and end of recovery for determination of muscle glycogen resynthesis rates, with further biopsies taken following a second bout of exhaustive exercise to determine differences in substrate availability relative to the initial sample taken following the first exercise bout. Phase I will inform whether a dose-response relationship exists between carbohydrate ingestion rate and muscle glycogen availability and/or the subsequent capacity for physical exercise. Phase II will determine whether such effects are dependent on glycogen availability per se or energy intake, potentially via protein mediated mechanisms. ISRCTN87937960.


Prognostic factors in thyroid tumours.
Using Cox's Proportional Hazard Model, we have demonstrated the influence of age, sex, microscopic tumour type, extent of primary tumour, nodal status and the presence of metastases on prognosis, in our population of 441 patients with thyroid carcinoma. The TNM classification contributes significantly to survival, but does not include other contributory prognostic variables, whereas the prognostic index developed by the EORTC thyroid study group, which takes account of age and histology, proved a reliable predictor of survival for our patient group.


In situ characterisation of nanostructured multiphase thermoelectric materials at elevated temperatures.
Multiphase thermoelectric materials have recently attracted considerable attention due to the high thermoelectric efficiencies which can be achieved in these compounds compared to their single-phase counterparts. However, there is very little known on the structural evolution of these phases as a function of temperature. In this work we performed an in situ high temperature structural characterisation of recently reported high efficiency p-type multiphase (PbTe)0.65(PbS)0.25(PbSe)0.1 compounds by hot stage transmission electron microscopy and high-resolution neutron powder diffraction. We observed the microstructural evolution of precipitates and determined the lattice parameters of phases as a function of temperature for materials, which have been heavily and lightly doped with sodium. The role of the sodium is to optimize the concentration of charge carriers. It has been shown to distribute heterogeneously between the phases in multiphase compounds. The dissolution of secondary phases is found to occur at elevated temperatures. Although sodium concentration produces no significant differences between the lattice constants of the phases and the dissolution sequence of precipitates, it affects quite significantly the kinetics of precipitation. The heavily doped samples reach structural thermodynamic equilibrium more quickly than the lightly doped compound. These results are a step forward in designing high performance multiphase thermoelectric materials.


Antibiotic allergy.
Antibiotics are the commonest cause of life-threatening immune-mediated drug reactions that are considered off-target, including anaphylaxis, and organ-specific and severe cutaneous adverse reactions. However, many antibiotic reactions documented as allergies were unknown or not remembered by the patient, cutaneous reactions unrelated to drug hypersensitivity, drug-infection interactions, or drug intolerances. Although such reactions pose negligible risk to patients, they currently represent a global threat to public health. Antibiotic allergy labels result in displacement of first-line therapies for antibiotic prophylaxis and treatment. A penicillin allergy label, in particular, is associated with increased use of broad-spectrum and non-β-lactam antibiotics, which results in increased adverse events and antibiotic resistance. Most patients labelled as allergic to penicillins are not allergic when appropriately stratified for risk, tested, and re-challenged. Given the public health importance of penicillin allergy, this Review provides a global update on antibiotic allergy epidemiology, classification, mechanisms, and management.


Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells.
Taurine-induced changes in the expression profiles of HepG2 cells were assessed using a cDNA microarray technology, and confirmed by real-time reverse transcription-polymerase chain reaction (RT-PCR) analyses. Of 8,298 human genes on the microarray, 128 genes (87 known genes) were up-regulated, and 349 (206 known genes) were down-regulated more than 2.0-fold by taurine. Among the 293 known genes regulated by taurine, a total of 44 genes were involved in signal transduction; 16 genes were up-regulated greater than 2.0-fold, and 28 genes were down-regulated more than 2.0-fold by taurine. The results of RT-PCR analyses for the five genes selected were consistent with our microarray data, although the fold changes in the expression level differed somewhat between the two analytical methods. Among signal transduction-related genes affected by taurine, four genes--mitogen-activated protein kinase (MAPK) kinase kinase 7, p21-activated kinase 4, sprouty homolog 2, and MAPK kinase 1--are implicated in the MAPK signaling pathway. Taurine also regulated the expression of signal transducer and activator of transcription (STAT) 3 gene involved in the Janus kinase-STAT pathway, and diacylglycerol kinase, zeta 104 kDa, the downstream mediator of the protein kinase C transmembrane signaling pathway. In conclusion, gene expression profiling of HepG2 cells treated with taurine provided us with new insights into the novel aspects of taurine as a possible regulator of MAPK signaling cascades and protein kinase C signaling pathways involved in cellular processes such as cell growth, differentiation, and apoptosis.


Pattern classification by adaptive machines.
Man's intelligent behavior is due in part to his ability to select, classify, and abstract significant information reaching him from his environment by way of his senses. This function, pattern recognition, has become a major focus of research by scientists working in the field of artificial intelligence. At the lowest level, pattern recognition reduces to pattern classification, which consists of the separation, into desired classes, of groups of objects, sounds, odors, events, properties, and the like; the separations are based on sets of measurements made on the entities being classified. The pattern classifier is composed of a data filter and a categorizer. The data filter selects the distinguishing features and represents them as sets of real numbers; each set is termed a pattern. The categorizer assigns each pattern to one of several desired classes. Patterns can be represented geometrically as points in an n-dimensional space; the n coordinates of each point are the numerical values of the features selected to represent the pattern. A pattern classification system separates an n-dimensional space into regions, each of which ideally contains points of only one class. One method to effect this separation is by means of ldquo;trainablerdquo; categorizers-major components of adaptive machines. They consist of networks whose internal parameters are varied according to a set of fixed rules during a training cycle. A statistically large sample of known patterns are presented, one at a time, to the networks; internal corrections are made each time a pattern is erroneously classified. Classifica-tion performance tends to improve as the set of known patterns is cycled repetitively through the machine. Finally, the adequacy of adaptation is tested by a separate set of similar patterns which have not been used in the training process. A number of different machine organizations and training rules have been developed and are being applied successfully to numerous classification problems. More difficult recognition problems requiring the aid of logioal tests and analysis, search and association, use the digital computer programmed to supplement the functions of the adaptive classifier.


Are endophenotypes based on measures of executive functions useful for molecular genetic studies of ADHD?
Behavioral genetic studies provide strong evidence that attention-deficit/hyperactivity disorder (ADHD) has a substantial genetic component. Yet, due to the complexity of the ADHD phenotype, questions remain as to the specific genes that contribute to this condition as well as the pathways from genes to behavior. Endophenotypes, or phenotypes that are more closely linked to the neurobiological substrate of a disorder, offer the potential to address these two issues simultaneously (Freedman, Adler, & Leonard, 1999). Thus far, potential endophenotypes for ADHD have not been systematically studied. The current paper reviews evidence supporting the use of deficits on neurocognitive measures of executive functions for this purpose. Such deficits are a correlate of ADHD and show preliminary evidence of heritability and association with relevant candidate genes. Nonetheless, studies that have assessed the familial and genetic overlap of neurocognitive impairments with ADHD have yielded inconsistent results. In order for executive function deficits to be used as an endophenotype for ADHD, we recommend greater attention to the neurocognitive heterogeneity of this disorder and to the precision of measurement of the neuropsychological tests employed. We also discuss empirical strategies that may be necessary to allow such research to progress prior to full resolution of the pathophysiological basis of ADHD.


Highly Stable Monocrystalline Silver Clusters for Plasmonic Applications.
Plasmonic sensor configurations utilizing localized plasmon resonances in silver nanostructures typically suffer from the rapid degradation of silver under ambient atmospheric conditions. In this work, we report on the fabrication and detailed characterization of ensembles of monocrystalline silver nanoparticles (NPs), which exhibit a long-term stability of optical properties under ambient conditions without any protective treatments. Ensembles with different densities (surface coverages) of size-selected NPs (mean diameters of 12.5 and 24 nm) on quartz substrates are fabricated using the cluster-beam technique and characterized by linear spectroscopy, two-photon-excited photoluminescence, surface-enhanced Raman scattering microscopy, and transmission electron, helium ion, and atomic force microscopies. It is found that the fabricated ensembles of monocrystalline silver NPs preserve their plasmonic properties (monitored with optical spectroscopy) and strong field enhancements (revealed by surface-enhanced Raman spectroscopy) at least 5 times longer as compared to chemically synthesized silver NPs with similar sizes. The obtained results are of high practical relevance for the further development of sensors, resonators, and metamaterials utilizing the plasmonic properties of silver NPs.


Development of a lateral flow assay for rapid detection of bovine antibody to Anaplasma marginale.
A rapid lateral flow assay for detection of bovine antibody to Anaplasma marginale was developed. The assay used a recombinant peptide of major surface protein 5 as the antigen and a monoclonal antibody specific for bovine IgG(1) conjugated with colloidal gold beads for detection. Serum and anticoagulated blood samples were obtained from cattle in an area where anaplasmosis was endemic. The samples were selected based on positive identification of the organism in blood smears. The unclotted blood samples were used for PCR determination of the presence of A. marginale while the sera were tested by a commercial competitive enzyme immunoassay (CELISA) and by the lateral flow assay (LFA). Similar samples, collected at a Canadian sales barn, were tested by the CELISA and LFA and 10% were tested by PCR for the presence of A. marginale nucleic acid. In addition, stored serum samples from a second endemic area were tested by CELISA and LFA. Of the 114 smear positive samples, all were positive by CELISA and LFA. All samples were also positive by PCR. Samples from Canadian sources (n=524) were negative in the CELISA but 11 sera gave false positive reactions in the LFA. All samples tested were PCR negative. Of 113 samples from herds with anaplasmosis, 53 were positive in the CELISA and 50 were LFA positive.


Studies of a South East Asian ant-plant association: protection of Macaranga trees by Crematogaster borneensis.
In the humid tropics of SE Asia there are some 14 myrmecophytic species of the pioneer tree genus Macaranga (Euphorbiaceae). In Peninsular Malaysia a close association exists between the trees and the small, non-stinging myrmicine Crematogaster borneensis. These ants feed mainly on food bodies provided by the plants and have their colonies inside the hollow internodes. In a ten months field study we were able to demonstrate for four Macaranga species (M. triloba, M. hypoleuca, M. hosei, M. hulletti) that host plants also benefit considerably from ant-occupation. Ants do not contribute to the nutrient demands of their host plant, they do, however, protect it against herbivores and plant competition. Cleaning behaviour of the ants results in the removal of potential hervivores already in their earliest developmental stages. Strong aggressiveness and a mass recruiting system enable the ants to defend the host plant against many herbivorous insects. This results in a significant decrease in leaf damage due to herbivores on ant-occupied compared to ant-free myrmecophytes as well as compared to non-myrmecophytic Macaranga species. Most important is the ants' defense of the host plant against plant competitors, especially vines, which are abundant in the well-lit pioneer habitats where Macaranga grows. Ants bite off any foreign plant part coming into contact with their host plant. Both ant-free myrmecophytes and non-myrmecophytic Macaranga species had a significantly higher incidence of vine growth than specimens with active ant colonies. This may be a factor of considerable importance allowing Macaranga plants to grow at sites of strongest competition.


Agomelatine strongly interacts with zwitterionic DPPC and charged DPPG membranes.
Depression is one of the most common psychiatric diseases in the population. Agomelatine is a novel antidepressant drug with melatonin receptor agonistic and serotonin 5-HT2C antagonistic properties. Furthermore, being a melatonergic drug, agomelatine has the potential of being used in therapeutic applications like melatonin as an antioxidant, anti-inflammatory and antiapoptotic drug. The action mechanism of agomelatine on the membrane structure has not been clarified yet. In the present study, we aimed to investigate the interaction of agomelatine with model membranes of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylgylcerol (DPPG) by Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). We found that agomelatine interacts with the head group in such a manner that it destabilizes the membrane architecture to a large extent. Thus, agomelatine causes alterations in the order, packing and dynamics of the DPPC and DPPG model membranes. Our results suggest that agomelatine strongly interacts with zwitterionic and charged membrane phospholipids. Because lipid structure and dynamics may have influence on the structure of membrane bound proteins and affect the signal transduction systems of membranes, these effects of agomelatine may be important in its action mechanism.


Cranberries and cranberry products: powerful in vitro, ex vivo, and in vivo sources of antioxidants.
Cranberry products and especially cranberry juice (CJ) have been consumed for health reasons primarily due to their effect on urinary tract infections. We investigated the quantity of both free and total (after hydrolysis) phenolic antioxidants in cranberry products using the Folin assay. The order of amount of total polyphenols in cranberry foods on a fresh weight basis was as follows: dried > frozen > sauce > jellied sauce. On a serving size basis for all cranberry products, the order was as follows: frozen > 100% juice > dried > 27% juice > sauce > jellied sauce. High fructose corn syrup (HFCS) is a major source of sugar consumption in the U.S. and contains both glucose and fructose, potential mediators of oxidative stress. We investigated the effect of the consumption of HFCS and ascorbate with CJ antioxidants or without CJ (control) given to 10 normal individuals after an overnight fast. Plasma antioxidant capacity, glucose, triglycerides, and ascorbate were measured 6 times over 7 h after the consumption of a single 240 mL serving of the two different beverages. The control HFCS caused a slight decrease in plasma antioxidant capacity at all time points and thus an oxidative stress in spite of the presence of ascorbate. CJ produced an increase in plasma antioxidant capacity that was significantly greater than control HFCS at all time points. Postprandial triglycerides, due to fructose in the beverages, were mainly responsible for the oxidative stress and were significantly correlated with the oxidative stress as measured by the antioxidant capacity. Cranberries are an excellent source of high quality antioxidants and should be examined in human supplementation studies.


Synthesis of phylogeny and taxonomy into a comprehensive tree of life.
Reconstructing the phylogenetic relationships that unite all lineages (the tree of life) is a grand challenge. The paucity of homologous character data across disparately related lineages currently renders direct phylogenetic inference untenable. To reconstruct a comprehensive tree of life, we therefore synthesized published phylogenies, together with taxonomic classifications for taxa never incorporated into a phylogeny. We present a draft tree containing 2.3 million tips-the Open Tree of Life. Realization of this tree required the assembly of two additional community resources: (i) a comprehensive global reference taxonomy and (ii) a database of published phylogenetic trees mapped to this taxonomy. Our open source framework facilitates community comment and contribution, enabling the tree to be continuously updated when new phylogenetic and taxonomic data become digitally available. Although data coverage and phylogenetic conflict across the Open Tree of Life illuminate gaps in both the underlying data available for phylogenetic reconstruction and the publication of trees as digital objects, the tree provides a compelling starting point for community contribution. This comprehensive tree will fuel fundamental research on the nature of biological diversity, ultimately providing up-to-date phylogenies for downstream applications in comparative biology, ecology, conservation biology, climate change, agriculture, and genomics.


Brain-derived neurotrophic factor regulates glucose metabolism by modulating energy balance in diabetic mice.
We previously reported that brain-derived neurotrophic factor (BDNF) regulates both food intake and blood glucose metabolism in rodent obese diabetic models such as C57BL/KsJ-lepr(db)/lepr(db) (db/db) mice. To elucidate the effect of BDNF on glucose metabolism, we designed a novel pellet pair-feeding apparatus to eliminate the effect of appetite alteration on glucose metabolism. The apparatus was used to synchronize food intake precisely between BDNF-treated and vehicle-treated db/db mice. It was shown using this pellet pair-feeding apparatus that BDNF administered daily (20 mg x kg(-1) x day(-1)) to db/db mice significantly lowered blood glucose compared with pellet pair-fed db/db mice. To evaluate the effect of BDNF on insulin action, we used streptozotocin-induced type 1 diabetic mice. In this case, BDNF did not lower blood glucose concentration but rather enhanced the hypoglycemic action of insulin. In hyperglycemic db/db mice, pancreatic insulin content was reduced and glucagon content was increased compared with normoglycemic db/m mice. BDNF administered to db/db mice significantly restored both pancreatic insulin and glucagon content. Histological observations of aldehyde-fuchsin staining and immunostaining with anti-insulin indicated that insulin-positive pancreatic beta-cells were extensively regranulated by BDNF administration. We also studied the effect of BDNF on KK mice, normoglycemic animals with impaired glucose tolerance. In these mice, BDNF administration improved insulin resistance in the oral glucose tolerance test. To elucidate how blood glucose was metabolized in BDNF-treated animals, we investigated the effect of BDNF on the energy metabolism of db/db mice. Body temperature and oxygen consumption of the pellet pair-fed vehicle-treated mice were remarkably lower than the ad libitum-fed vehicle-treated mice. Daily BDNF administration for 3 weeks completely ameliorated both of the reductions. Finally, to clarify its action mechanism, the effect of intracerebroventricular administration of BDNF on db/db mice was examined. Here, a small dose of BDNF was found to be effective in lowering blood glucose concentration. This indicates that BDNF regulates glucose metabolism by acting directly on the brain.


Antitumor effects of a water-soluble extract from Maitake (Grifola frondosa) on human gastric cancer cell lines.
We investigated the effects of a water-soluble extract of Maitake (Grifola frondosa), a Japanese edible mushroom, on the proliferation and cell death of four human gastric cancer cell lines (TMK-1, MKN28, MKN45 and MKN74). The Maitake extract (ME) inhibited the proliferation of all four cell lines in a time-dependent manner. The inhibition was most pronounced in TMK-1 cells, which exhibited up to 90% inhibition after treatment with 10% ME for 3 days. Staining of ME-treated TMK-1 cells with Hoechst 33258 revealed increased numbers of nuclear condensations and apoptotic bodies. Induction of apoptosis was confirmed by fluorescence-activated cell sorting analyses. Western blot analyses of TMK-1 cells after ME treatment revealed increases in intracytoplasmic cytochrome c and cleavage of caspase-3 and poly(ADP-ribose) polymerase, but no expression of p21 or Bax. The caspase-3 protease activities in lysates of TMK-1 cells treated with 1% or 10% ME were about three times higher than those in control cells. The proliferation of TMK-1 cells was hardly affected by the caspase-3 inhibitor z-DEVD-fmk. Taken together, these results suggest that ME induces apoptosis of TMK-1 cells by caspase-3-dependent and -independent pathways, resulting in potential antitumor effects on gastric cancer.


Serum-Free Culture System for Spontaneous Human Mesenchymal Stem Cell Spheroid Formation.
Human mesenchymal stem cells (hMSCs) are widely used in clinical research because of their multipotential, immunomodulatory, and reparative properties. Previous studies determined that hMSC spheroids from a three-dimensional (3D) culture possess higher therapeutic efficacy than conventional hMSCs from a monolayer (2D) culture. To date, various 3D culture methods have been developed to form hMSC spheroids but most of them used culture medium containing fetal bovine serum (FBS), which is not suitable for further clinical use. Here, we demonstrate that dissociated single MSCs seeded in induced pluripotent stem medium (MiPS) adhere loosely to the dish and spontaneously migrate to form spheroids during day 3 to day 6. Through component deletion screening and complementation experiments, the knockout serum replacement (KSR) was identified as necessary and sufficient for hMSC spheroid formation. Transcriptome analysis showed that the overall expression profiles were highly similar between 2D culture with FBS and KSR-derived spheroids. Interestingly, genes related to inflammatory response, immune response, and angiogenesis were upregulated in spheroids at day 6 and qPCR results further validated the increased expression level of related genes, including STC1, CCL7, HGF, IL24, and TGFB3. When spheroids were replated in normal FBS medium, cells formed a typical spindle-shaped morphology and FACS results showed that the recovered cells retained MSC-specific surface markers, such as CD73, CD90, and CD105. In summary, we developed a practical and convenient method to generate hMSC spheroids for clinical research and therapy.


Functional connectivity and laterality of the motor and sensory components in the volitional swallowing network.
Functional neuroimaging has shown that multiple brain regions are active during volitional swallowing. Little is known, however, about which regions integrate motor execution and sensory feedback in the swallowing system. Although unilateral brain lesions in either hemisphere can produce swallowing deficits, some functional neuroimaging studies indicate that the left hemisphere has greater activation in certain sensory and motor-related swallowing regions. In this study, correlation coefficients were computed for five seed regions during volitional saliva swallowing to determine the functional relationships of these regions with the rest of the brain: the anterior and posterior insula, inferior frontal gyrus (BA44), primary sensory cortex (S1), and primary motor cortex (M1). A laterality index (LI) was derived that accounts for relative differences in total, positive connected voxels for the left/right hemisphere seeds. Clusters of significantly connected voxels were greater from the anterior and posterior insula than from the other three seed regions. Interactions of the insula with other brain regions were greater on the left than on the right during volitional swallowing. Group means showed laterality in the anterior insula (LI = 0.25) and the posterior insula (LI = 0.33). BA44 showed a lesser degree of difference in left versus right hemisphere interactions (LI = 0.12) while S1 did not show lateralization (LI = 0.02) and M1 showed some predominance of interactions in the right hemisphere (LI = -0.19). The greater connectivity from the left hemisphere insula to brain regions within and across hemispheres suggests that the insula is a primary integrative region for volitional swallowing in humans.


Salud Mesoamérica 2015 Initiative: design, implementation, and baseline findings.
Health has improved markedly in Mesoamerica, the region consisting of southern Mexico and Central America, over the past decade. Despite this progress, there remain substantial inequalities in health outcomes, access, and quality of medical care between and within countries. Poor, indigenous, and rural populations have considerably worse health indicators than national or regional averages. In an effort to address these health inequalities, the Salud Mesoamérica 2015 Initiative (SM2015), a results-based financing initiative, was established. For each of the eight participating countries, health targets were set to measure the progress of improvements in maternal and child health produced by the Initiative. To establish a baseline, we conducted censuses of 90,000 households, completed 20,225 household interviews, and surveyed 479 health facilities in the poorest areas of Mesoamerica. Pairing health facility and household surveys allows us to link barriers to care and health outcomes with health system infrastructure components and quality of health services. Indicators varied significantly within and between countries. Anemia was most prevalent in Panama and least prevalent in Honduras. Anemia varied by age, with the highest levels observed among children aged 0 to 11 months in all settings. Belize had the highest proportion of institutional deliveries (99%), while Guatemala had the lowest (24%). The proportion of women with four antenatal care visits with a skilled attendant was highest in El Salvador (90%) and the lowest in Guatemala (20%). Availability of contraceptives also varied. The availability of condoms ranged from 83% in Nicaragua to 97% in Honduras. Oral contraceptive pills and injectable contraceptives were available in just 75% of facilities in Panama. IUDs were observed in only 21.5% of facilities surveyed in El Salvador. These data provide a baseline of much-needed information for evidence-based action on health throughout Mesoamerica. Our baseline estimates reflect large disparities in health indicators within and between countries and will facilitate the evaluation of interventions and investments deployed in the region over the next three to five years. SM2015's innovative monitoring and evaluation framework will allow health officials with limited resources to identify and target areas of greatest need.


New perspectives on bioactivity of olive oil: evidence from animal models, human interventions and the use of urinary proteomic biomarkers.
Olive oil (OO) is the primary source of fat in the Mediterranean diet and has been associated with longevity and a lower incidence of chronic diseases, particularly CHD. Cardioprotective effects of OO consumption have been widely related with improved lipoprotein profile, endothelial function and inflammation, linked to health claims of oleic acid and phenolic content of OO. With CVD being a leading cause of death worldwide, a review of the potential mechanisms underpinning the impact of OO in the prevention of disease is warranted. The current body of evidence relies on mechanistic studies involving animal and cell-based models, epidemiological studies of OO intake and risk factor, small- and large-scale human interventions, and the emerging use of novel biomarker techniques associated with disease risk. Although model systems are important for mechanistic research nutrition, methodologies and experimental designs with strong translational value are still lacking. The present review critically appraises the available evidence to date, with particular focus on emerging novel biomarkers for disease risk assessment. New perspectives on OO research are outlined, especially those with scope to clarify key mechanisms by which OO consumption exerts health benefits. The use of urinary proteomic biomarkers, as highly specific disease biomarkers, is highlighted towards a higher translational approach involving OO in nutritional recommendations.


Tire wear particles in the aquatic environment - A review on generation, analysis, occurrence, fate and effects.
Tire wear particles (TWP), generated from tire material during use on roads have gained increasing attention as part of organic particulate contaminants, such as microplastic, in aquatic environments. The available information on properties and generation of TWP, analytical techniques to determine TWP, emissions, occurrence and behavior and ecotoxicological effects of TWP are reviewed with a focus on surface water as a potential receptor. TWP emissions are traffic related and contribute 5-30% to non-exhaust emissions from traffic. The mass of TWP generated is estimated at 1,327,000 t/a for the European Union, 1,120,000 t/a for the United States and 133,000 t/a for Germany. For Germany, this is equivalent to four times the amount of pesticides used. The mass of TWP ultimately entering the aquatic environment strongly depends on the extent of collection and treatment of road runoff, which is highly variable. For the German highways it is estimated that up to 11,000 t/a of TWP reach surface waters. Data on TWP concentrations in the environment, including surface waters are fragmentary, which is also due to the lack of suitable analytical methods for their determination. Information on TWP properties such as density and size distribution are missing; this hampers assessing the fate of TWP in the aquatic environment. Effects in the aquatic environment may stem from TWP itself or from compounds released from TWP. It is concluded that reliable knowledge on transport mechanism to surface waters, concentrations in surface waters and sediments, effects of aging, environmental half-lives of TWP as well as effects on aquatic organisms are missing. These aspects need to be addressed to allow for the assessment of risk of TWP in an aquatic environment.


Gender differences in plasma biomarker levels in a cohort of COPD patients: a pilot study.
Little is known about gender differences in plasma biomarker levels in patients with chronic obstructive pulmonary disease (COPD). There are differences in serum biomarker levels between women and men with COPD. Explore gender differences in plasma biomarker levels in patients with COPD and smokers without COPD. We measured plasma levels of IL-6, IL-8, IL-16, MCP-1, MMP-9, PARC and VEGF in 80 smokers without COPD (40 males, 40 females) and 152 stable COPD patients (76 males, 76 females) with similar airflow obstruction. We determined anthropometrics, smoking history, lung function, exercise tolerance, body composition, BODE index, co-morbidities and quality of life. We then explored associations between plasma biomarkers levels and the clinical characteristics of the patients and also with the clinical and physiological variables known to predict outcome in COPD. The plasma biomarkers level explored were similar in men and women without COPD. In contrast, in patients with COPD the median value in pg/mL of IL-6 (6.26 vs 8.0, p = 0.03), IL-16 (390 vs 321, p = 0.009) and VEGF (50 vs 87, p = 0.02) differed between women and men. Adjusted for smoking history, gender was independently associated with IL-16, PARC and VEGF levels. There were also gender differences in the associations between IL-6, IL-16 and VEGF and physiologic variables that predict outcomes. In stable COPD patients with similar airflow obstruction, there are gender differences in plasma biomarker levels and in the association between biomarker levels and important clinical or physiological variables. Further studies should confirm our findings.


A new target for gold(I) compounds: glutathione-S-transferase inhibition by auranofin.
Nowadays, gold compounds occupy a relevant position constituting a promising class of experimental anticancer metallodrugs. Several research efforts have been devoted to the investigations of the pharmacological properties of gold(I) complexes bearing phosphine ligands, such as the antiarthritic drug auranofin, that has also been shown to produce anticancer effects in vitro. In spite of the numerous studies that appeared in the literature the biological mechanisms of action of auranofin and analogues are still controversial. Here, we report on the inhibition effects of glutathione S-transferase P1-1 (GST P1-1) exerted by auranofin. The compound was able to inhibit GST P1-1 with a calculated IC(50) of 32.9±0.5μM. Interestingly, the inhibition of GST P1-1 and its cysteine mutants by the gold(I) compound is essentially the same, suggesting that probably the cysteine residues are not so essential for enzyme inactivation in contrast to other reported inhibitors. High-resolution electrospray ionisation Fourier transform ion cyclotron mass spectrometry (ESI FT-ICR MS) studies allowed characterising the binding of the compound with GST enzymes at a molecular level, confirming that similar gold binding sites may be present in the wild-type protein and its Cys mutants.


The ethics of psychiatric care and research in resource-poor settings: The case of a research trial in a prayer camp in Ghana.
A communication in the January 2018 issue of the British Journal of Psychiatry detailed a clinical trial on persons with mental illness (PWMI), some of whom were in chains in a prayer camp setting in Ghana. The camp's advertised mission statement was to "set free those held captive by Satan" through its "ministry of fasting and prayer". This article considers the potential ethical problems raised by the clinical trial on chained PWMI against the background of Ghanaian ethnoanthropological beliefs. It highlights two significant categories of ethical issues: first, those associated with standard psychiatric practice in the treatment of persons with severe mental illness (specifically, the issue of informed consent and the use of physical restraint and seclusion in psychiatric practice); and second, issues pertaining to the study under discussion (specifically, issues of study methodology and the principle of equipoise; biological determinism as against the multifactorial paradigm of mental illness/practice, implied or assumed; misalignment between the research methodology, results, and the underlying aim of the study, bordering on epistemology and pragmatism/values; and finally, the association of the trial researchers with the practice of chaining). This article, in highlighting the ethical issues raised by the clinical trial in question, attempts to suggest what Ghanaian healthcare professionals, policymakers, and the national government can do (and how) to institute workable, enforceable measures towards ending the practice of chaining PWMI in Ghana.


Ameliorative Effects of Honey, Propolis, Pollen, and Royal Jelly Mixture against Chronic Toxicity of Sumithion Insecticide in White Albino Rats.
Sumithion (Fenitrothion) (SUM) is an organophosphorus insecticide used to combat a wide variety of plant pests. Exposure to SUM causes significant toxicity to the brain, liver, kidney, and reproductive organs through, for example, binding to DNA, and it induces DNA damage, which ends with oxidative stress. Therefore, the present study aimed to examine the protective role of bee products: a mixture of honey, propolis, palm pollen, and royal jelly (HPPJ) against SUM-induced toxicity. Twenty-four male albino rats (Rattus norvegicus) were classified into four groups, each containing six rats: control (corn oil), SUM (85 mg/kg; 1/20 LD50), HPPJ, and SUM + HPPJ once daily for 28 consecutive days. Blood samples were gently collected in sterilized ethylenediaminetetraacetic acid (EDTA) tubes for blood picture analyses and tubes without anticoagulant for serum isolation. Serum was used for assays of enzymatic and biochemical characteristics. The results revealed that SUM increased the weights of the liver, kidney, and brain as well as the enzymatic activity of glutathione peroxidase (GP), serum superoxide dismutase (SOD), and glutathione-S-transferase (GST). Additionally, SUM significantly increased the activity of lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and γ-glutamyltransferase (γ-GT) and glucose, uric acid, and creatinine contents, while decreasing the acetylcholine esterase (AChE) activity and total lipids and total protein content. Furthermore, because of the inclusion of phenolic, flavonoids, terpenoids, and sugars, the HPPJ mixture counteracted the hematological, renal, and hepatic toxicity of SUM exposure.


Mental Health Conditions and Unplanned Hospital Readmissions in Children.
Mental health conditions (MHCs) are prevalent among hospitalized children and could influence the success of hospital discharge. We assessed the relationship between MHCs and 30-day readmissions. This retrospective, cross-sectional study of the 2013 Nationwide Readmissions Database included 512,997 hospitalizations of patients ages 3 to 21 years for the 10 medical and 10 procedure conditions with the highest number of 30-day readmissions. MHCs were identified by using the International Classification of Diseases, 9th Revision-Clinical Modification codes. We derived logistic regression models to measure the associations between MHC and 30-day, all-cause, unplanned readmissions, adjusting for demographic, clinical, and hospital characteristics. An MHC was present in 17.5% of medical and 13.1% of procedure index hospitalizations. Readmission rates were 17.0% and 6.2% for medical and procedure hospitalizations, respectively. In the multivariable analysis, compared with hospitalizations with no MHC, hospitalizations with MHCs had higher odds of readmission for medical admissions (adjusted odds ratio [AOR], 1.23; 95% confidence interval [CI], 1.19-1.26] and procedure admissions (AOR, 1.24; 95% CI, 1.15-1.33). Three types of MHCs were associated with higher odds of readmission for both medical and procedure hospitalizations: depression (medical AOR, 1.57; 95% CI, 1.49-1.66; procedure AOR, 1.39; 95% CI, 1.17-1.65), substance abuse (medical AOR, 1.24; 95% CI, 1.18-1.30; procedure AOR, 1.26; 95% CI, 1.11-1.43), and multiple MHCs (medical AOR, 1.43; 95% CI, 1.37-1.50; procedure AOR, 1.26; 95% CI, 1.11-1.44). MHCs are associated with a higher likelihood of hospital readmission in children admitted for medical conditions and procedures. Understanding the influence of MHCs on readmissions could guide strategic planning to reduce unplanned readmissions for children with cooccurring physical and mental health conditions.


Willingness to pay for methadone maintenance treatment in Vietnamese epicentres of injection-drug-driven HIV infection.
Willingness to pay for methadone maintenance treatment (MMT) in three Vietnamese epicentres of injection-drug-driven human immunodeficiency virus (HIV) infection was assessed. A convenience sample of 1016 patients receiving HIV treatment in seven clinics was enrolled during 2012. Contingent valuation was used to assess willingness to pay. Interviewers reviewed adverse consequences of injection drug use and the benefits of MMT. Interviewers then described the government's plan to scale up MMT and the financial barriers to scale-up. Willingness to pay was assessed using double-bounded binary questions and a follow-up open-ended question. Point and interval data models were used to estimate maximum willingness to pay. A total of 548 non-drug-users and 468 injection drug users were enrolled; 988 were willing to pay for MMT. Monthly mean willingness to pay among non-drug-users, 347 drug users not receiving MMT and 121 drug users receiving MMT was 10.7 United States dollars [US$] (35.7% of treatment costs), US$ 21.1 (70.3%) and US$ 26.2 (87.3%), respectively (mean: US$ 15.9; 95% confidence interval, CI: 13.6-18.1). Fifty per cent of drug users were willing to pay 50% of MMT costs. Residence in households with low monthly per capita income and poor health status predicted willingness to pay less among drug users; educational level, employment status, health status and current antiretroviral therapy receipt predicted willingness to pay less among non-drug-users. Willingness to pay for MMT was very high, supporting implementation of a co-payment programme.


Investigation of mammographic breast density as a risk factor for ovarian cancer.
Endogenous hormones and growth factors that increase mammographic breast density could increase ovarian cancer risk. We examined whether high breast density is associated with ovarian cancer risk. We conducted a cohort study of 724,603 women aged 40 to 79 years with 2,506,732 mammograms participating in the Breast Cancer Surveillance Consortium from 1995 to 2009. Incident epithelial ovarian cancer was diagnosed in 1373 women. We used partly conditional Cox regression to estimate the association between breast density and 5-year risk of incident epithelial ovarian cancer overall and stratified by 10-year age group. All statistical tests were two-sided. Compared with women with scattered fibroglandular densities, women with heterogeneously dense and extremely dense breast tissue had 20% and 18% increased 5-year risk of incident epithelial ovarian cancer (hazard ratio [HR] = 1.20, 95% confidence interval [CI] = 1.06 to 1.36; HR = 1.18, 95% CI = 0.93 to 1.50, respectively; P(trend) = .01). Among women aged 50 to 59 years, we observed a trend in elevated risk associated with increased breast density (P(trend) = .02); women with heterogeneously and extremely dense breast tissue had 30% (HR = 1.30; 95% CI = 1.03 to 1.64) and 65% (HR = 1.65; 95% CI = 1.12 to 2.44) increased risk, respectively, compared with women with scattered fibroglandular densities. The pattern was similar but not statistically significant at age 40 to 49 years. There were no consistent patterns of breast density and ovarian cancer risk at age 60 to 79 years. Dense breast tissue was associated with a modest increase in 5-year ovarian cancer risk in women aged 50 to 59 years but was not associated with ovarian cancer at ages 40 to 49 or 60 to 79 years.


Fabrication and characterization of complex nanoparticles based on carboxymethyl short chain amylose and chitosan by ionic gelation.
We aimed to investigate whether the combination of the modification of short chain amylose (SCA) with chitosan (CS) through the electrostatic interaction could be considered as a candidate for oral delivery of bioactive ingredients. Carboxymethyl short chain amylose (CMSCA) was synthesized by reacting SCA with monochloroacetic acid. The changes in SCA levels after the reaction were investigated by zeta-potential determination, Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry, thermogravimetry and derivative thermogravimetry. Complex nanoparticles (NPs) were then synthesized using CMSCA and CS by ionic gelation. FTIR spectral analysis revealed that the complex NPs were synthesized by hydrogen bonding and electrostatic interactions between CMSCA and CS. CMSCA/CS NPs show an insulin encapsulation efficiency of 85.2% and exhibit sustained release of insulin in vitro. CMSCA/CS NPs were observed to show excellent cytocompatibility by cell culture. These findings demonstrated that CMSCA/CS NPs constructed by the ionic gelation method could be further exploited as a potential oral delivery system for peptide drugs.