Data reuse and the open data citation advantage.
Background. Attribution to the original contributor upon reuse of published data is important both as a reward for data creators and to document the provenance of research findings. Previous studies have found that papers with publicly available datasets receive a higher number of citations than similar studies without available data. However, few previous analyses have had the statistical power to control for the many variables known to predict citation rate, which has led to uncertain estimates of the "citation benefit". Furthermore, little is known about patterns in data reuse over time and across datasets. Method and Results. Here, we look at citation rates while controlling for many known citation predictors and investigate the variability of data reuse. In a multivariate regression on 10,555 studies that created gene expression microarray data, we found that studies that made data available in a public repository received 9% (95% confidence interval: 5% to 13%) more citations than similar studies for which the data was not made available. Date of publication, journal impact factor, open access status, number of authors, first and last author publication history, corresponding author country, institution citation history, and study topic were included as covariates. The citation benefit varied with date of dataset deposition: a citation benefit was most clear for papers published in 2004 and 2005, at about 30%. Authors published most papers using their own datasets within two years of their first publication on the dataset, whereas data reuse papers published by third-party investigators continued to accumulate for at least six years. To study patterns of data reuse directly, we compiled 9,724 instances of third party data reuse via mention of GEO or ArrayExpress accession numbers in the full text of papers. The level of third-party data use was high: for 100 datasets deposited in year 0, we estimated that 40 papers in PubMed reused a dataset by year 2, 100 by year 4, and more than 150 data reuse papers had been published by year 5. Data reuse was distributed across a broad base of datasets: a very conservative estimate found that 20% of the datasets deposited between 2003 and 2007 had been reused at least once by third parties. Conclusion. After accounting for other factors affecting citation rate, we find a robust citation benefit from open data, although a smaller one than previously reported. We conclude there is a direct effect of third-party data reuse that persists for years beyond the time when researchers have published most of the papers reusing their own data. Other factors that may also contribute to the citation benefit are considered. We further conclude that, at least for gene expression microarray data, a substantial fraction of archived datasets are reused, and that the intensity of dataset reuse has been steadily increasing since 2003.


TU-G-BRB-02: A New Mathematical Framework for IMRT Inverse Planning with Voxel-Dependent Optimization Parameters.
To establish a new mathematical framework for IMRT treatment optimization with voxel-dependent optimization parameters. In IMRT inverse treatment planning, a physician seeks for a plan to deliver a prescribed dose to the target while sparing the nearby healthy tissues. The conflict between these objectives makes the multi-criteria optimization an appropriate tool. Traditionally, a clinically acceptable plan can be generated by fine-tuning organ-based parameters. We establish a new mathematical framework by using voxel-based parameters for optimization. We introduce three different Pareto surfaces, prove the relationship between those surfaces, and compare voxel-based and organ-based methods. We prove some new theorems providing conditions under which the Pareto optimality is guaranteed. The new mathematical framework has shown that: 1) Using an increasing voxel penalty function with an increasing derivative, in particular the popular power function, it is possible to explore the entire Pareto surface by changing voxel-based weighting factors, which increases the chances of getting more desirable plan. 2) The Pareto optimality is always guaranteed by adjusting voxel-based weighting factors. 3) If the plan is initially produced by adjusting organ-based weighting factors, it is impossible to improve all the DVH curves at the same time by adjusting voxel-based weighting factors. 4) A larger Pareto surface is explored by changing voxel-based weighting factors than by changing organ-based weighting factors, possibly leading to a plan with better trade-offs. 5) The Pareto optimality is not necessarily guaranteed while we are adjusting the voxel reference doses, and hence, adjusting voxel-based weighting factors is preferred in terms of preserving the Pareto optimality. We have developed a mathematical framework for IMRT optimization using voxel-based parameters. We can improve the plan quality by adjusting voxel-based weighting factors after organ-based parameter adjustment. This work is supported by Varian Medical Systems through a Master Research Agreement.


Pituitary-adrenal response to static exercise in man.
1. Changes in plasma concentrations of catecholamines and cortisol were measured before and after static exercise performed by the subject pushing with both legs against a strain-gauge bar. No marked changes in plasma catecholamine were observed but plasma cortisol increased after the subject pushed for 3 min at 50% of maximum force. 2. Holding a 20 kg weight for 5 min in one hand caused a rise in plasma cortisol and in plasma ACTH but no changes in growth hormone were observed.


Stigmatization of people who inject drugs (PWID) by pharmacists in Tajikistan: sociocultural context and implications for a pharmacy-based prevention approach.
Pharmacies are an important source of sterile syringes for people who inject drugs (PWID) in Tajikistan who are under high risk of HIV and hepatitis C virus. Accessibility of sterile syringes at pharmacies without prescription may depend on pharmacists' attitudes towards PWID. This qualitative inquiry examines meanings and processes of stigmatization of PWID among pharmacists and pharmacy students in Tajikistan. We conducted semi-structured interviews with 19 pharmacists and 9 students (N = 28) in the cities of Dushanbe and Kulob, Tajikistan. The interview topics included personal attitudes towards drug use and PWID, encounters with PWID, awareness and beliefs related to drug dependence and HIV, and attitudes and practices related to providing syringes to PWID. Interview transcripts were analysed using thematic analysis methods. The main themes included the significance of religion in defining attitudes towards drug use, labelling of PWID, negative stereotypes (PWID are prone to crime, violence, and irrational aggression; inflict harm to families and society; are able to control drug use), emotions triggered by PWID (fear, sympathy) and discrimination against PWID (rejection, isolation, ostracism, limiting resources to PWID). The religious ban on drug use and pharmacists' moral and legal responsibility for the consequences of drug use were frequently mentioned as reasons for rejecting syringe sales. Still, many participants acknowledged the need for distributing syringes to PWID to prevent HIV. Stigma against PWID in Tajikistan plays an important role in shaping pharmacists' attitudes towards provision of services to this population. Local sociocultural context, in particular religious beliefs and social conservatism, may facilitate stigmatizing beliefs.


Comparative analysis of mRNA targets for human PUF-family proteins suggests extensive interaction with the miRNA regulatory system.
Genome-wide identification of mRNAs regulated by RNA-binding proteins is crucial to uncover post-transcriptional gene regulatory systems. The conserved PUF family RNA-binding proteins repress gene expression post-transcriptionally by binding to sequence elements in 3'-UTRs of mRNAs. Despite their well-studied implications for development and neurogenesis in metazoa, the mammalian PUF family members are only poorly characterized and mRNA targets are largely unknown. We have systematically identified the mRNAs associated with the two human PUF proteins, PUM1 and PUM2, by the recovery of endogenously formed ribonucleoprotein complexes and the analysis of associated RNAs with DNA microarrays. A largely overlapping set comprised of hundreds of mRNAs were reproducibly associated with the paralogous PUM proteins, many of them encoding functionally related proteins. A characteristic PUF-binding motif was highly enriched among PUM bound messages and validated with RNA pull-down experiments. Moreover, PUF motifs as well as surrounding sequences exhibit higher conservation in PUM bound messages as opposed to transcripts that were not found to be associated, suggesting that PUM function may be modulated by other factors that bind conserved elements. Strikingly, we found that PUF motifs are enriched around predicted miRNA binding sites and that high-confidence miRNA binding sites are significantly enriched in the 3'-UTRs of experimentally determined PUM1 and PUM2 targets, strongly suggesting an interaction of human PUM proteins with the miRNA regulatory system. Our work suggests extensive connections between the RBP and miRNA post-transcriptional regulatory systems and provides a framework for deciphering the molecular mechanism by which PUF proteins regulate their target mRNAs.


Characterization and water activation behavior of tourmaline nanoparticles.
Tourmaline nanoparticles were prepared by using a wet mechanochemisty method. The X-ray diffraction (XRD) and scanning electron microscopy (SEM) results showed that the tourmaline grain size is in the range from tens of nanometers to several hundred nanometers. Through characterization by Fourier transform infrared spectroscope, it was found that the milled tourmaline had a better far infrared emitting performance due to the increase of radiation surface area. The structure change of liquid water clusters induced by the addition of tourmaline nanoparticles was observed by nuclear magnetic resonance (NMR). The results showed that the addition of tourmaline nanoparticles reduced the 17O NMR full width at half maximum intensity (FWHM) for treated water and the volume of water molecule clusters. The feature of activated water was enhanced with decreasing tourmaline nanoparticles size due to the cooperation of strong surface electric field and high far infrared emissivity. Moreover the activation time can be maintained at 480 h suggesting the potential application of tourmaline in wastewater treatment.


Role of the chemokine decoy receptor D6 in balancing inflammation, immune activation, and antimicrobial resistance in Mycobacterium tuberculosis infection.
D6 is a decoy and scavenger receptor for inflammatory CC chemokines. D6-deficient mice were rapidly killed by intranasal administration of low doses of Mycobacterium tuberculosis. The death of D6(-/-) mice was associated with a dramatic local and systemic inflammatory response with levels of M. tuberculosis colony-forming units similar to control D6-proficient mice. D6-deficient mice showed an increased numbers of mononuclear cells (macrophages, dendritic cells, and CD4 and CD8 T lymphocytes) infiltrating inflamed tissues and lymph nodes, as well as abnormal increased concentrations of CC chemokines (CCL2, CCL3, CCL4, and CCL5) and proinflammatory cytokines (tumor necrosis factor alpha, interleukin 1beta, and interferon gamma) in bronchoalveolar lavage and serum. High levels of inflammatory cytokines in D6(-/-) infected mice were associated with liver and kidney damage, resulting in both liver and renal failure. Blocking inflammatory CC chemokines with a cocktail of antibodies reversed the inflammatory phenotype of D6(-/-) mice but led to less controlled growth of M. tuberculosis. Thus, the D6 decoy receptor plays a key role in setting the balance between antimicrobial resistance, immune activation, and inflammation in M. tuberculosis infection.


Elevated serum sFlt-1/Ang-2 ratio in women with preeclampsia.
An imbalance of angiogenesis-associated factors may predispose to preeclampsia. Here, we determined the ratio of serum concentration of soluble fms-like tyrosine kinase 1 (sFlt-1), a natural inhibitor of pro-angiogenic vascular endothelial growth factor (VEGF) relative to angiopoietin-2 (Ang-2), a natural antagonist of angiopoietin-1 (Ang-1) involved in promoting angiogenesis in the presence of VEGF, in women with preeclampsia. The levels of serum sFlt-1 and Ang-2 were measured by enzyme-linked immunosorbent assay. Significant decrease of serum Ang-2 and the increase of sFlt-1 were observed in women with preeclampsia as compared to healthy pregnant women. The serum sFlt-1/Ang-2 ratio was strikingly increased in preeclamptic women in contrast to healthy pregnant women exhibiting lower value similar to non-pregnant women. The serum sFlt-1 concentrations tended to positively correlate with mean blood pressure (BP) in preeclamptic women, but not in healthy pregnant women. A cut-off value >0.25 in the serum sFlt-1/Ang-2 ratio showed 87.1% sensitivity and 82.8% specificity in differentiating preeclamptic women from healthy pregnant women. The serum sFlt-1/Ang-2 ratio is significantly elevated in preeclamptic women as compared to healthy pregnant women. Remarkable difference of sFlt-1/Ang-2 ratio between these two groups with excellent specificity and sensitivity suggests the clinical usefulness of the serum sFlt-1/Ang-2 ratio in diagnosing and potentially predicting the onset of preeclampsia.


Breast motion asymmetry during running.
Breast asymmetry is common in females, despite a similar driving force; dynamic activity may result in asymmetrical breast motion. This preliminary study investigated how breast categorisation (left/right or dominant/non-dominant) may affect breast support recommendations and its relationship with breast pain. Ten females ran on a treadmill at 10 kph in three breast supports (no bra, everyday bra, sports bra). Five reflective markers on the thorax and nipples were tracked using infrared cameras (200 Hz) during five running gait cycles in each breast support. Multiplanar displacements of both breasts were calculated relative to the thorax. Although the maximum individual participant difference was 2.4 cm (mediolaterally) between the left and right breast, no left/right differences were found in any direction or support condition. Notably, correlations between breast pain and anterioposterior breast displacement were stronger with the left breast (r = 0.614) and moderate with the right breast (r = 0.456). Following participant categorisation according to the greatest magnitude of superioinferior breast displacement (dominant breast), results showed significant differences in displacement for all directions across different breast supports. When using breast kinematic data to examine relationships with breast pain or to recommend breast support requirements, data on both breasts should be collected.


Body mass index across midlife and cognitive change in late life.
High midlife body mass index (BMI) has been linked to a greater risk of dementia in late life, but few have studied the effect of BMI across midlife on cognitive abilities and cognitive change in a dementia-free sample. We investigated the association between BMI, measured twice across midlife (mean age 40 and 61 years, respectively), and cognitive change in four domains across two decades in the Swedish Adoption/Twin Study of Aging. Latent growth curve models fitted to data from 657 non-demented participants showed that persons who were overweight/obese in early midlife had significantly lower cognitive performance across domains in late life and significantly steeper decline in perceptual speed, adjusting for cardio-metabolic factors. Both underweight and overweight/obesity in late midlife were associated with lower cognitive abilities in late life. However, the association between underweight and low cognitive abilities did not remain significant when weight decline between early and late midlife was controlled for. There is a negative effect on cognitive abilities later in life related to being overweight/obese across midlife. Moreover, weight decline across midlife rather than low weight in late midlife per se was associated with low cognitive abilities. Weight patterns across midlife may be prodromal markers of late life cognitive health.


A survey of canine filarial diseases of veterinary and public health significance in India.
Dirofilaria spp., Acanthocheilonema spp. and Brugia spp. have all been reported in Indian dogs. In previous studies, diagnosis was made by morphological identification only. This is the first geographically stratified cross-sectional study in India to determine the prevalence and geographical distribution of canine filarial species of veterinary and public health importance, using a combination of conventional and molecular diagnostic techniques. A total of 139 from 525 dogs (26.5%; 95% CI 22.7, 30.3) were positive for microfilariae. The most common species of canine filaria identified in this study was A. reconditum (9.3%) followed by D. repens (6.7%) and D. immitis (1.5%). Three out of 525 dogs were found to have mixed infections on PCR. The morphological and molecular evidence on the sequence of the 18S gene and phylogenetic analysis of the ITS-2 region provided strong evidence that the canine microfilariae discovered in the Himalayan city of Ladakh belong to a novel species of Acanthocheilonema. Two dogs in Ladakh were also found to have mixed infections of the novel species described above and a unique microfilaria which morphologically resembled Microfilaria auquieri Foley, 1921. At least six species of filarial nematode are now known to infect dogs in India, two of which were reported for the first time in this study. The study also confirms and extends the geographical distribution of canine heartworm (D. immitis) which overlaps with D. repens, emphasising the importance for veterinary clinicians and diagnostic laboratories to utilise immunodiagnostic tests that will not cross-react between those two filarial species. From a public health viewpoint, the distribution and prevalences of these nematodes warrant an appropriate prophylaxis to be administered to dogs.


Nitric Oxide Releasing Nanoparticles as a Strategy to Improve Current Onychomycosis Treatments.
Topical antimicrobials are the ideal mode of onychomycosis treatment for efficient drug delivery and avoidance of sytemic effects associated with oral medications. However, high treatment costs, tissue penetration limitations, and low cure rates have continued to pose major challenges. To capitalize on the progress made by topical efinaconazole solution, efinaconazole was combined with inexpensive, previously-characterized nitric oxide releasing nanoparticles (NO-np), which have been shown to offer sustained nitric oxide release over time and enhanced barrier penetration, while exerting broad spectrum antimicrobial and immunomodulating properties. NO-np were combined with efinaconazole in varying concentrations and applied against reference strains of Trichophyton rubrum using a checkerboard method. Results demonstrated synergism of NO-np+efinaconazole against T. rubrum, which is noteworthy given the barriers present in the topical treatment of onychomycosis, and the multiple potential benefits offered by NO-np. Overall, this study illustrates the untapped potential of nanotechnology in the treatment of disorders of the skin, hair, and nails where drug delivery remains a challenge. J Drugs Dermatol. 2018;17(7):717-720.


Optical amplification of two different propagation modes in organic small molecular waveguide structure.
We investigate the emission spectra from the edge of optically pumped waveguide. The waveguide is based on vacuum-deposited thin films of small molecular, 2,5,2',5'-tetrakis(2,2-diphenylvinyl)biphenyl (TDPVBi). Narrowed emissions are observed both at high (> 6 KW/cm2) and low (< 1 W/cm2) pump power sources, which are attributed to two different propagation modes in the asymmetric slab waveguides, guided mode and cutoff mode, respectively. The peak wavelengths of the guided mode appear at the maximum of the photoluminescence (PL) spectrum of the TDPVBi film. In contrast, both the peak wavelength and polarization of the cutoff mode are thickness dependent. The optical gains of the two modes are measured by the variable stripe length (VSL) method. The amplification with an exceptional low threshold for the cutoff mode has been demonstrated. Our results suggest that the cutoff mode is a promising route for the reduction of lasing threshold.


Adult and childhood acute lymphoblastic leukemia: clinico-biological differences based on CD34 antigen expression.
The prognostic significance of CD34 antigen expression in acute lymphoblastic leukemias (ALL), especially in adult patients, is still not well established. In the present report we analyzed a series of biological and clinical findings from 128 ALL patients in order to evaluate the possible clinical significance of this marker. The clinical and biological significance of CD34 expression, an early marker of hemopoietic cells, was analyzed by flow cytometry in a series of 128 patients affected by ALL, including 78 adults and 50 children under 15 years old. Overall, 68.7% of patients showed significant ( > 10%) CD34 expression. There was no difference between CD34+ and CD34- ALL with respect to age, sex, FAB morphology, hepatosplenomegaly, Plt count, Hb level, DNA index, P-170 expression. CD34+ ALL displayed a significantly lower frequency of extramedullary involvement, a lower LDH level and lower WBC count, lower proliferative activity (as evaluated by the Ki67 monoclonal antibody) than CD34- ALL. CD34 expression was also associated with early phenotypes in both B- and T-ALL, co-expression of myeloid antigens, and the presence of the Ph1 chromosome. Due to a different distribution of prognostic factors investigated, DFS and OS were both significantly better in CD34+ than in CD34- childhood ALL, whereas no statistical difference was found in adults. Multivariate analyses confirmed these data in children. Expression of the CD34 antigen is a positive prognostic factor in childhood ALL. In adult ALL the presence of this marker on leukemic cell does not seem to influence the clinical outcome of these patients.


Preparing student midwives for professional practice: Evaluation of a student e-portfolio assessment item.
Capstone experiences facilitate consolidation and application of previous learning, strengthening professional identity and competency. This study evaluates the effectiveness and acceptability of a capstone assessment item, in the form of an e-portfolio, designed to identify and demonstrate preparedness for professional midwifery practice. A sequential explanatory strategy occurred within a mixed method research design. Final year Bachelor of Midwifery students at an Australian university, having completed the e-portfolio assessment, participated in two phases of data collection; an initial online-survey, followed by in-depth exploration of emergent concepts within a focus group. Analysis of the quantitative data identified completing the e-portfolio assessment increased students' skills, knowledge and confidence and promoted reflection and critical thinking. Three themes emerged from the qualitative data; acknowledging growth and development; transitioning to practice, and knowing 'who I am and where I am going'. The e-portfolio assessment meets the aims of a capstone assessment and provides an appropriate framework and authentic opportunity for students to identify and demonstrate their level of preparedness for professional practice, determine their ongoing learning needs and develop strategies for achieving them. The assessment item provides an opportunity to develop and articulate a personal practice philosophy and embeds the principles of lifelong learning.


Autophagy impairment: a crossroad between neurodegeneration and tauopathies.
Most neurodegenerative diseases involve the accumulation of misfolded proteins in the nervous system. Impairment of protein degradation pathways such as autophagy is emerging as a consistent and transversal pathological phenomenon in neurodegenerative diseases, including Alzheimer's, Huntington's, and Parkinson's disease. Genetic inactivation of autophagy in mice has demonstrated a key role of the pathway in maintaining protein homeostasis in the brain, triggering massive neuronal loss and the accumulation of abnormal protein inclusions. However, the mechanism underlying neurodegeneration due to autophagy impairment remains elusive. A paper in Molecular Neurodegeneration from Abeliovich's group now suggests a role for phosphorylation of Tau and the activation of glycogen synthase kinase 3β (GSK3β) in driving neurodegeneration in autophagy-deficient neurons. We discuss the implications of this study for understanding the factors driving neurofibrillary tangle formation in Alzheimer's disease and tauopathies.


The influence of solution environment on the nucleation kinetics and crystallisability of para-aminobenzoic acid.
The influence of solvent type on the solution thermodynamics, nucleation-kinetics and crystal growth of alpha para-aminobenzoic acid (PABA) crystallising from supersaturated ethanol, acetonitrile and water solutions, is examined using poly-thermal analysis of the metastable zone width. Application of a recently proposed model for analysis of crystallisation kinetics (J. Cryst. Growth, 2010, 312, 698-704) indicates a solvent and concentration dependence of the nucleation mechanism and key nucleation parameters for the alpha form of PABA. The mechanism of nucleation is found to change from instantaneous to progressive with decreasing concentration and also when changing the solvent from ethanol to acetonitrile to water. The dependence of the nucleation mechanism is correlated to the kinetic component of the nucleation rate through calculated values of instantaneously nucleated crystallites, which increase from 1.40 × 109 m-3 in ethanol to 1.08 × 1010 m-3 in acetonitrile to 2.58 × 1010 m-3 in water. This in combination with low calculated number concentrations of interfacial tension between 1.13 and 2.71 mJ m-2, supports the conclusion that the kinetic component of the nucleation rate is more limiting when crystallising PABA from ethanol solutions in comparison to water solutions. This finding is further supported by molecular dynamics simulations of the solvation free energy of PABA, which is found to be greatest in water, -42.4 kJ mol-1 and lowest in ethanol, -58.5 kJ mol-1.


A day in the life of PubMed: analysis of a typical day's query log.
To characterize PubMed usage over a typical day and compare it to previous studies of user behavior on Web search engines. We performed a lexical and semantic analysis of 2,689,166 queries issued on PubMed over 24 consecutive hours on a typical day. We measured the number of queries, number of distinct users, queries per user, terms per query, common terms, Boolean operator use, common phrases, result set size, MeSH categories, used semantic measurements to group queries into sessions, and studied the addition and removal of terms from consecutive queries to gauge search strategies. The size of the result sets from a sample of queries showed a bimodal distribution, with peaks at approximately 3 and 100 results, suggesting that a large group of queries was tightly focused and another was broad. Like Web search engine sessions, most PubMed sessions consisted of a single query. However, PubMed queries contained more terms. PubMed's usage profile should be considered when educating users, building user interfaces, and developing future biomedical information retrieval systems.


A model for cleavage plane determination in early amphibian and fish embryos.
Current models for cleavage plane determination propose that metaphase spindles are positioned and oriented by interactions of their astral microtubules with the cellular cortex, followed by cleavage in the plane of the metaphase plate [1, 2]. We show that in early frog and fish embryos, where cells are unusually large, astral microtubules in metaphase are too short to position and orient the spindle. Rather, the preceding interphase aster centers and orients a pair of centrosomes prior to nuclear envelope breakdown, and the spindle assembles between these prepositioned centrosomes. Interphase asters center and orient centrosomes with dynein-mediated pulling forces. These forces act before astral microtubules contact the cortex; thus, dynein must pull from sites in the cytoplasm, not the cell cortex as is usually proposed for smaller cells. Aster shape is determined by interactions of the expanding periphery with the cell cortex or with an interaction zone that forms between sister-asters in telophase. We propose a model to explain cleavage plane geometry in which the length of astral microtubules is limited by interaction with these boundaries, causing length asymmetries. Dynein anchored in the cytoplasm then generates length-dependent pulling forces, which move and orient centrosomes.


The plain abdominal roentgenogram in the management of encopresis.
To determine whether fecal retention in encopretic children can be assessed objectively using the plain abdominal roentgenogram and whether roentgenographic evidence of fecal retention is associated with clinical findings on presentation in encopretic children. Retrospective case studies. Two pediatric incontinence clinics. Sixty children (72% male), aged 4 to 18 years (mean, 8 years), who met Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria for the diagnosis of encopresis. All had a plain abdominal roentgenogram obtained on presentation. None. Using a systematic assessment tool with good interrater reliability (kappa = 0.65), 78% (47) of the children had fecal retention by roentgenographic criteria on presentation, while 22% (13) did not. Retentive encopretic children were less likely to have a history of difficult toilet training (P = .018) than nonretentive encopretic children. There was no association between fecal retention and several clinical factors, including historical features commonly attributed to fecal retention. Retentive encopretic children were no more likely to have a palpable abdominal mass than nonretentive encopretic children, but they were more likely to have excessive stool on rectal examination (P = .015). Using the plain abdominal roentgenogram as the gold standard, the rectal examination showed a positive predictive value of 84.8% and a negative predictive value of 50% in assessing fecal retention. Fecal retention in encopretic children can be assessed objectively from a plain abdominal roentgenogram. Most, but not all, encopretic children present with fecal retention. A positive rectal examination is strongly predictive of fecal retention, in which case a roentgenogram is not necessary to make that diagnosis. A negative rectal examination may not rule out fecal retention, in which case an abdominal roentgenogram may be useful to make that diagnosis.


A cyclic-RGD-BioShuttle functionalized with TMZ by DARinv "Click Chemistry" targeted to αvβ3 integrin for therapy.
Clinical experiences often document, that a successful tumor control requires high doses of drug applications. It is widely believed that unavoidable adverse reactions could be minimized by using gene-therapeutic strategies protecting the tumor-surrounding healthy tissue as well as the bone-marrow. One new approach in this direction is the use of "Targeted Therapies" realizing a selective drug targeting to gain effectual amounts at the target site, even with drastically reduced application doses. MCF-7 breast cancer cells expressing the α(v)β(3) [alpha(v)beta(3)] integrin receptor are considered as appropriate candidates for such a targeted therapy. The modularly composed BioShuttle carrier consisting of different units designed to facilitate the passage across the cell membranes and for subcellular addressing of diagnostic and/or therapeutic molecules could be considered as an eligible delivery platform. Here we used the cyclic RGD-BioShuttle as a carrier for temozolomide (TMZ) at the α(v)β(3) integrin receptor realizing local TMZ concentrations sufficient for cell killing. The IC50 values are 12 µMol/L in the case of cRGD-BioShuttle-TMZ and 100 µMol/L for underivatized TMZ, which confirms the advantage of TMZ reformulation to realize local concentrations sufficient for cell killing. Our paper focuses on the design, synthesis and application of the cRGD-BioShuttle conjugate composed of the cyclic RGD, a α(v)β(3) integrin-ligand, ligated to the cytotoxic drug TMZ. The ligation was carried out by the Diels Alder Reaction with inverse electron demand (DAR(inv)).


Mitochondrial copy number is associated with colorectal cancer risk.
Mitochondria are eukaryotic organelles responsible for energy production. Quantitative changes in human mitochondrial DNA (mtDNA) copy number have been implicated in various cancer types. Data from prospective cohort studies on mtDNA copy number and colorectal cancer risk have been lacking. We evaluated the association between mtDNA copy number in peripheral blood and colorectal cancer risk in a nested case-control study of 422 colorectal cancer cases (168 cases with pre-diagnostic blood and 254 cases with post-diagnostic blood) and 874 controls who were free of colorectal cancer among participants of the Singapore Chinese Health Study. The relative mtDNA copy number was measured using real-time PCR. Unconditional logistic regression methods were employed to examine the association between mtDNA copy number and colorectal cancer risk. There was a U-shaped relationship between the relative mtDNA copy number and colorectal cancer risk. Compared with the 2nd quartile, the OR (95% confidence intervals) for subjects in the lowest and highest quartiles of relative mtDNA copy numbers were 1.81 (1.13-2.89) and 3.40 (2.15-5.36), respectively (P(curvilinearity) <0.0001). This U-shaped relationship was present in both men and women, similar for colon cancer and rectal cancer, and independent of the timing of blood draw with regard to cancer diagnosis. This is the first prospectively designed study to show a U-shaped association between the relative mtDNA copy number and risk of colorectal cancer. The findings of the present study support that mtDNA may play a critical role in the colorectal carcinogenesis in humans.


Optical tractography of the mouse heart using polarization-sensitive optical coherence tomography.
We developed a method to image myocardial fiber architecture in the mouse heart using a Jones matrix-based polarization-sensitive optical coherence tomography (PSOCT) system. The "cross-helical" laminar structure of myocardial fibers can be clearly visualized using this technology. The obtained myocardial fiber organization agrees well with existing knowledge acquired using conventional histology and diffusion tensor magnetic resonance imaging.


Cracking the code for H5N1-bird flu and beyond.
Influenza virus remains a significant threat to humanity despite the discovery of novel anti-viral therapies and the continuing development of seasonal vaccines. The reason for this ongoing concern is that the development of drug resistance to anti-virals has rapidly occurred and the currently developed vaccines are typically only effective against a specific influenza virus strain. The continual emergence of new influenza virus strains that may lead to the next human pandemic has inspired much research into a better understanding of the virus, particularly the role(s) of carbohydrates in the virus' lifecycle. Much of this research is directed towards next generation anti-influenza drugs. Important advances in the interrogation of influenza virus' surface glycoprotein haemagglutinin by NMR spectroscopy have been made in recent times. An overview of some of these advances is provided.


Induction of CD8(+) T cell responses and protective efficacy following microneedle-mediated delivery of a live adenovirus-vectored malaria vaccine.
There is an urgent need for improvements in vaccine delivery technologies. This is particularly pertinent for vaccination programmes within regions of limited resources, such as those required for adequate provision for disposal of used needles. Microneedles are micron-sized structures that penetrate the stratum corneum of the skin, creating temporary conduits for the needle-free delivery of drugs or vaccines. Here, we aimed to investigate immunity induced by the recombinant simian adenovirus-vectored vaccine ChAd63.ME-TRAP; currently undergoing clinical assessment as a candidate malaria vaccine, when delivered percutaneously by silicon microneedle arrays. In mice, we demonstrate that microneedle-mediated delivery of ChAd63.ME-TRAP induced similar numbers of transgene-specific CD8(+) T cells compared to intradermal (ID) administration with needle-and-syringe, following a single immunisation and after a ChAd63/MVA heterologous prime-boost schedule. When mice immunised with ChAd63/MVA were challenged with live Plasmodium berghei sporozoites, microneedle-mediated ChAd63.ME-TRAP priming demonstrated equivalent protective efficacy as did ID immunisation. Furthermore, responses following ChAd63/MVA immunisation correlated with a specific design parameter of the array used ('total array volume'). The level of transgene expression at the immunisation site and skin-draining lymph node (dLN) was also linked to total array volume. These findings have implications for defining silicon microneedle array design for use with live, vectored vaccines.


Duration of Internet use and adverse psychosocial effects among European adolescents.
Despite the significant contributions from previous studies about the prevalence of problematic Internet use (PIU) among adolescents in Europe, important questions remain regarding adverse consequences of PIU. This study aims to assess the relation between duration of Internet use and adverse psychosocial effects among adolescents from six European countries. The final sample included 7,351 adolescents (50.8% male and 49.2% female; mean age: 14.6±1.90) recruited from randomly selected schools within the six study sites. Results showed that 12.9% of adolescents used Internet more than 20 hours per week. There was a significant relationship between duration of Internet use and frequency of alcohol, tobacco, cannabis and other illegal drug use. Duration of Internet use is also significantly associated with school problems, with use of slot machines and with other psychosocial problems. These findings highlight the need to strengthen preventive efforts for reducing PIU and related consequences among adolescents. Key Words: Internet, adolescents, psychosocial problems.


Interactions between Human Liver Fatty Acid Binding Protein and Peroxisome Proliferator Activated Receptor Selective Drugs.
Fatty acid binding proteins (FABPs) act as intracellular shuttles for fatty acids as well as lipophilic xenobiotics to the nucleus, where these ligands are released to a group of nuclear receptors called the peroxisome proliferator activated receptors (PPARs). PPAR mediated gene activation is ultimately involved in maintenance of cellular homeostasis through the transcriptional regulation of metabolic enzymes and transporters that target the activating ligand. Here we show that liver- (L-) FABP displays a high binding affinity for PPAR subtype selective drugs. NMR chemical shift perturbation mapping and proteolytic protection experiments show that the binding of the PPAR subtype selective drugs produces conformational changes that stabilize the portal region of L-FABP. NMR chemical shift perturbation studies also revealed that L-FABP can form a complex with the PPAR ligand binding domain (LBD) of PPAR α . This protein-protein interaction may represent a mechanism for facilitating the activation of PPAR transcriptional activity via the direct channeling of ligands between the binding pocket of L-FABP and the PPAR α LBD. The role of L-FABP in the delivery of ligands directly to PPAR α via this channeling mechanism has important implications for regulatory pathways that mediate xenobiotic responses and host protection in tissues such as the small intestine and the liver where L-FABP is highly expressed.


The role of glycogen synthase kinase 3 (GSK3) in cancer with emphasis on ovarian cancer development and progression: A comprehensive review.
Glycogen synthase kinase 3 (GSK3) is a monomeric serine-threonine kinase discovered in 1980 in a rat skeletal muscle. It has been involved in various cellular processes including embryogenesis, immune response, inflammation, apoptosis, autophagy, wound healing, neurodegeneration, and carcinogenesis. GSK3 exists in two different isoforms, GSK3α and GSK3β, both containing seven antiparallel beta-plates, a short linking part and an alpha helix, but coded by different genes and variously expressed in human tissues. In the current review, we comprehensively appraise the current literature on the role of GSK3 in various cancers with emphasis on ovarian carcinoma. Our findings indicate that the role of GSK3 in ovarian cancer development cannot be decisively determined as the currently available data support both prooncogenic and tumor-suppressive effects. Likewise, the clinical impact of GSK3 expression on ovarian cancer patients and its potential therapeutic implications are also limited. Further studies are needed to fully elucidate the pathophysiological and clinical implications of GSK3 activity in ovarian cancer.


Outcomes of Left Main Percutaneous Coronary Intervention.
To study the outcomes of left main percutaneous coronary artery (LMCA) revascularisation. A descriptive study. The Aga Khan University Hospital (AKUH), Karachi, from February till July 2016. The study included all adult patients aged 18 years or more, who underwent percutaneous LMCA revascularisation at study centre from April 2006 till April 2015. In-hospital outcomes were ascertained of patients via charts along with telephonic follow-up for outcome ascertainment at 1-year and 5-year. Results were expressed in terms of means and standard deviation for quantitative variables and percentages for qualitative variables. Of the 86 patients, the mean age was 66.05 ±12.6 years and 69% (59 cases, n=86) of them were males. Sixteen (18.6%) patients presented with cardiogenic shock and 17.4% (15 cases, n=86) required mechanical ventilation upon arrival. Among the 86 patients, 23.3% (20 patients, n=86) underwent PCI because of unstable condition for CABG and refusal by the surgeons. Mean follow up time for participants was 40.5 ±25.7 months with mean length of hospital stay of 4.36 ±2.4 days. In-hospital mortality was 12.8%, while mortality at 1-year and at mean follow-up was 7.3% and 6.9%, respectively. LM percutaneous coronary intervention is a viable option for patients who are hemodynamicaly unstable and require urgent revascularisation or for patients denying bypass surgery due to other reasons in Pakistan. Prospective studies in future may be required to evaluate the role of PCI for LM lesions in elective setting in contrast to existing treatment options.


The cost effectiveness of ivabradine in the treatment of chronic heart failure from the U.K. National Health Service perspective.
Ivabradine, a specific heart rate lowering therapy, has been shown in a randomised placebo-controlled study, Systolic HF Treatment with the If Inhibitor Ivabradine Trial (SHIfT), to significantly reduce the composite end point of cardiovascular death and hospitalisation for worsening heart failure (HF) in patients with systolic HF who are in sinus rhythm and with a heart rate ≥70 bpm, when added to optimised medical therapy (HR: 0.82, 95% CI 0.75 to 0.90, p<0.0001). We assessed the cost effectiveness of ivabradine, from a UK National Health Service perspective, based on the results of SHIfT. A Markov model estimated the cost effectiveness of ivabradine compared with standard care for two cohorts of patients with HF (heart rate ≥75 bpm in line with the EU labelled indication; and heart rate ≥70 bpm in line with the SHIfT study population). Modelled outcomes included death, hospitalisation, quality of life and New York Heart Association class. Total costs and quality adjusted life years (QALYs) for ivabradine and standard care were estimated over a lifetime horizon. The incremental cost per additional QALY for ivabradine plus standard care versus standard care has been estimated as £8498 for heart rate ≥75 bpm and £13 764 for heart rate ≥70 bpm. Ivabradine is expected to have a 95% chance of being cost-effective in the EU licensed population using the current National Institute for Health and Care Excellence cost effectiveness threshold of £20 000 per QALY. These results were robust in sensitivity analyses. This economic evaluation suggests that the use of ivabradine is likely to be cost-effective in eligible patients with HF from a UK National Health Service perspective.


ACVR1 mutations in DIPG: lessons learned from FOP.
Whole-genome sequencing studies have recently identified a quarter of cases of the rare childhood brainstem tumor diffuse intrinsic pontine glioma to harbor somatic mutations in ACVR1. This gene encodes the type I bone morphogenic protein receptor ALK2, with the residues affected identical to those that, when mutated in the germline, give rise to the congenital malformation syndrome fibrodysplasia ossificans progressiva (FOP), resulting in the transformation of soft tissue into bone. This unexpected link points toward the importance of developmental biology processes in tumorigenesis and provides an extensive experience in mechanistic understanding and drug development hard-won by FOP researchers to pediatric neurooncology. Here, we review the literature in both fields and identify potential areas for collaboration and rapid advancement for patients of both diseases.


Luteolin suppresses the JAK/STAT pathway in a cellular model of intestinal inflammation.
Current treatment strategies for inflammatory bowel diseases (IBDs) are associated with a lower efficacy and with several side effects that strongly affect the quality of life of IBD patients. Consequently, the development of new therapies, combining efficacy and safety is an important goal in the field of intestinal inflammation. In this context, evidence supports that polyphenols can be promising candidates due to their ability to modulate intracellular inflammatory signalling cascades. Luteolin, a naturally occurring flavonoid, exhibits anti-inflammatory properties in several models of inflammation. However, its action against intestinal inflammation has been poorly explored. Therefore, there is a lack of scientific knowledge about the potential impact of luteolin in the intestinal inflammation, particularly regarding the underlying molecular mechanisms by which luteolin can exert its anti-inflammatory action. We assessed the potential anti-inflammatory effect of luteolin in a cellular model of intestinal inflammation using cytokine-stimulated HT-29 colon epithelial cells, and the underlying key molecular mechanisms were identified. Luteolin significantly inhibited interleukine-8 (IL-8) production, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression and nitric oxide (˙NO) overproduction induced by cytokines, indicating that luteolin negatively modulates key inflammatory signalling cascades underlying intestinal inflammation. Mechanistically, the inhibition of the JAK/STAT pathway was identified as a critical mechanism by which luteolin exerts its intestinal anti-inflammatory action. This study uncovers novel molecular mechanisms by which luteolin may act against intestinal inflammation, which might support the use of luteolin as a future therapeutic strategy in IBD.


Estrogen Receptor 1 (ESR1) Enhances Slc2a4/GLUT4 Expression by a SP1 Cooperative Mechanism.
Background: Estrogens are involved in glycemic regulation, playing an important role in the development and/or progression of insulin resistance. For that, estrogens regulate the expression of the glucose transporter protein GLUT4 (codified by the solute carrier family 2 member 4 gene, Slc2a4), thus modulating adipose and muscle glucose disposal. This regulation is a balance between ESR1-mediated enhancer effect and ESR2-mediated repressor effect on Slc2a4 gene. However, molecular mechanisms involved in these effects are poorly understood. Since the specificity protein 1 (SP1) participates in several ESR-mediated genomic regulations, the aim of the present study is to investigate the participation of SP1 in the ESR1/2-mediated regulation of Slc2a4 gene. Methods: Differentiated 3T3-L1 adipocytes were 24-hour challenged with 10 nM estradiol (E2) and 10 nM ESR1 agonist (PPT) or 100 nM ESR2 agonist (DPN), added or not with E2. Slc2a4 and Sp1 mRNAs (RT-qPCR), total GLUT4 and nuclear ESR1, ESR2 and SP1 proteins (Western blotting), SP1 binding activity into Slc2a4 promoter (EMSA), and nuclear complexation of SP1/ESR1 (immunoprecipitation) were analyzed. Results: E2 and PPT increased (25-50%) whereas DPN reduced (20-45%) Slc2a4 and GLUT4 expression. Nuclear content of ESR1 and ESR2 remained unchanged. Nuclear content of SP1 increased (50 to 90%) by PPT and DPN added or not with E2; the highest effect observed with PPT alone. PPT also increased the nuclear content of SP1/ESR1 complex and the SP1 binding into the Slc2a4 promoter. Conclusions: ESR1 activation in adipocytes increased the nuclear content of SP1 protein, the SP1/ESR1 interaction and SP1 binding into the Slc2a4 gene promoter, culminating with increased Slc2a4/GLUT4 expression. No involvement of SP1 seems to occur in ESR2-mediated repressor effect on Slc2a4. We expect that this ESR1/SP1 cooperative effect can contribute to the development of new approaches for prevention or treatment of insulin resistance and diabetes mellitus.


Comparison of Outcomes among Adult Patients with Nosocomial Bacteremia Caused by Methicillin-Susceptible and Methicillin-Resistant Staphylococcus aureus: A Retrospective Cohort Study.
Several studies have shown that patients with bacteremia caused by methicillin-resistant Staphylococcus aureus (MRSA) have worse outcomes than those with bacteremia caused by methicillin-susceptible S. aureus (MSSA). However, only a limited number of studies have stratified the MRSA isolates into healthcare-associated (HA-) and community-associated (CA-) MRSA strains in such a comparison. This three-year retrospective cohort study, enrolling adult patients with nosocomial S. aureus bacteremia (SAB), was designed to investigate whether CA-MRSA and/or HA-MRSA strains were associated with different outcomes in comparison to MSSA in such a setting. The drug susceptibilities and staphylococcal cassette chromosome mec (SCCmec) types were determined for all of the causative isolates available. The MRSA bacteremia was further categorized into those caused by CA-MRSA strains (CA-MRSA-S bacteremia) when the causative isolates carried the type IV or V SCCmec element, those caused by HA-MRSA strains (HA-MRSA-S bacteremia) when the isolates carried the type I, II, or III SCCmec element, or unclassified MRSA bacteremia when the isolates were not available. The relevant demographic, clinical, and laboratory data were collected by reviewing the patients' charts. The primary outcome was all-cause in-hospital mortality. A total of 353 patients were studied. The overall in-hospital mortality rate was 32.6%, with 23.3% in MSSA, 30.5% in CA-MRSA-S, 47.5% in HA-MRSA-S, and 35.3% in unclassified MRSA bacteremia, respectively. The multivariate analysis showed that HA-MRSA-S, but not CA-MRSA-S, bacteremia was associated with a significantly worse outcome compared with MSSA. The other risk factors independently associated with all-cause in-hospital mortality included the Charlson co-morbidity index, septic shock, thrombocytopenia, and persistent bacteremia. Resistance to linezolid and daptomycin was found among the MRSA isolates. The present study showed that bacteremia caused by HA-MRSA-S, but not CA-MRSA-S, was an independent risk factor for all-cause in-hospital mortality in patients with nosocomial SAB. Continuous monitoring regarding the susceptibilities of MRSA to linezolid and daptomycin is necessary.


A comprehensive investigation of the synthesis of prebiotic galactooligosaccharides by whole cells of Bifidobacterium bifidum NCIMB 41171.
The synthesis of galactooligosaccharides (GOS) by whole cells of Bifidobacterium bifidum NCIMB 41171 was investigated by developing a set of mathematical models. These were second order polynomial equations, which described responses related to the production of GOS constituents, the selectivity of lactose conversion into GOS, and the relative composition of the produced GOS mixture, as a function of the amount of biocatalyst, temperature, initial lactose concentration, and time. The synthesis reactions were followed for up to 36 h. Samples were withdrawn every 4 h, tested for β-galactosidase activity, and analysed for their carbohydrate content. GOS synthesis was well explained by the models, which were all significant (P<0.001). The GOS yield increased as temperature increased from 40°C to 60°C, as transgalactosylation became more pronounced compared to hydrolysis. The relative composition of GOS produced changed significantly with the initial lactose concentration (P<0.001); higher ratios of tri-, tetra-, and penta-galactooligosaccharides to transgalactosylated disaccharides were obtained as lactose concentration increased. Time was a critical factor, as a balanced state between GOS synthesis and hydrolysis was roughly attained in most cases between 12 and 20 h, and was followed by more pronounced GOS hydrolysis than synthesis.


Instrumented treadmill for measuring vertical ground reaction forces in horses.
To develop and validate a novel instrumented treadmill capable of determining vertical ground reaction forces of all 4 limbs simultaneously in horses. Data obtained while a horse was walking and trotting on the treadmill. 18 piezo-electric force transducers were mounted between the treadmill frame and supporting steel platform to measure the actual forces at the corresponding bearing points. Each of the 18 sensor forces is equal to the sum of the unknown hoof forces weighted with the transfer coefficients of the corresponding force application points. The 4 force traces were calculated, solving at each time point the resulting equation system, using the Gaussian least-squares method. System validation comprised the following tests: determination of the survey accuracy of the positioning system, determination of the natural frequencies of the system, linearity test of the force transfer to the individual sensors, determination of superimposed forces with the treadmill-integrated force measuring system (TiF) in a static configuration, and comparison of vertical ground reaction forces determined simultaneously by use of TiF and force shoes mounted on the forelimbs of a horse. Comparison between static test loads and TiF-calculated forces revealed deviations of < 1.4%. Force traces of TiF-calculated values and those recorded by use of the force shoes were highly correlated (r > or = 0.998). This instrumented treadmill allows a reliable assessment of load distribution and interlimb coordination in a short period and, therefore, is suitable for use in experimental and clinical investigations.


Minority drug-resistant HIV-1 variants in treatment naïve East-African and Caucasian patients detected by allele-specific real-time PCR.
To assess the presence of two major non-nucleoside reverse transcriptase inhibitors (NNRTI) drug resistance mutations (DRMs), Y181C and K103N, in minor viral quasispecies of treatment naïve HIV-1 infected East-African and Swedish patients by allele-specific polymerase chain reaction (AS-PCR). Treatment naïve adults (n=191) with three epidemiological backgrounds were included: 92 Ethiopians living in Ethiopia; 55 East-Africans who had migrated to Sweden; and 44 Caucasians living in Sweden. The pol gene was analysed by standard population sequencing and by AS-PCR for the detection of Y181C and K103N. The Y181C was detected in the minority quasispecies of six Ethiopians (6.5%), in two Caucasians (4.5%), and in one East-African (1.8%). The K103N was detected in one East- African (1.8%), by both methods. The proportion of mutants ranged from 0.25% to 17.5%. Additional DRMs were found in all three treatment naïve patient groups by population sequencing. Major NNRTI mutations can be found by AS-PCR in minor quasispecies of treatment naïve HIV-1 infected Ethiopians living in Ethiopia, in East-African and Caucasian patients living in Sweden in whom population sequencing reveal wild-type virus only. Surveys with standard sequencing are likely to underestimate transmitted drug resistance and the presence of resistant minor quasispecies in treatment naïve patients should be topic for future large scale studies.


A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease.
Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic forms of the disease. Using a patient-based in vitro model of PARK7-linked PD, we identified a U1-dependent splicing defect causing a drastic reduction in DJ-1 protein and, consequently, mitochondrial dysfunction. Targeting defective exon skipping with genetically engineered U1-snRNA recovered DJ-1 protein expression in neuronal precursor cells and differentiated neurons. After prioritization of candidate drugs, we identified and validated a combinatorial treatment with the small-molecule compounds rectifier of aberrant splicing (RECTAS) and phenylbutyric acid, which restored DJ-1 protein and mitochondrial dysfunction in patient-derived fibroblasts as well as dopaminergic neuronal cell loss in mutant midbrain organoids. Our analysis of a large number of exomes revealed that U1 splice-site mutations were enriched in sporadic PD patients. Therefore, our study suggests an alternative strategy to restore cellular abnormalities in in vitro models of PD and provides a proof of concept for neuroprotection based on precision medicine strategies in PD.


The framing effect and skin conductance responses.
Individuals often rely on simple heuristics when they face complex choice situations under uncertainty. Traditionally, it has been proposed that cognitive processes are the main driver to evaluate different choice options and to finally reach a decision. Growing evidence, however, highlights a strong interrelation between judgment and decision-making (JDM) on the one hand, and emotional processes on the other hand. This also seems to apply to judgmental heuristics, i.e., decision processes that are typically considered to be fast and intuitive. In this study, participants are exposed to different probabilities of receiving an unpleasant electric shock. Information about electric shock probabilities is either positively or negatively framed. Integrated skin conductance responses (ISCRs) while waiting for electric shock realization are used as an indicator for participants' emotional arousal. This measure is compared to objective probabilities. I find evidence for a relation between emotional body reactions measured by ISCRs and the framing effect. Under negative frames, participants show significantly higher ISCRs while waiting for an electric shock to be delivered than under positive frames. This result might contribute to a better understanding of the psychological processes underlying JDM. Further studies are necessary to reveal the causality underlying this finding, i.e., whether emotional processes influence JDM or vice versa.


The limits of top-down control of visual attention.
The extent to which spatial selection is driven by the goals of the observer and by the properties of the environment is one of the major issues in the field of visual attention. Here we review recent experimental evidence from behavioral and eye movement studies suggesting that top-down control has temporal and spatial limits. More specifically, we argue that the first feedforward sweep of information is bottom-up, and that top-down control can influence selection only after the sweep is completed. In addition, top-down control can limit spatial selection through adjusting the size of attentional window, an area of visual space which receives priority in information sampling. Finally, we discuss the evidence found using brain imaging techniques for top-down control in an attempt to reconcile it with behavioral findings. We conclude by discussing theoretical implications of these results for the current models of visual selection.


Sleep Complaints of Postmenopausal Women.
OBJECTIVE: To study correlates of sleep problems in postmenopausal women. METHODS: Baseline questionnaire items related to sleep patterns and problems were administered to 98,705 postmenopausal women as part of the Clinical Trial and the Observational Study of the Women's Health Initiative. RESULTS: Less than 27% of the sample reported sleeping 8 hours or more. Many women reported that at least once a week they awoke several times at night (61%), fell asleep during quiet activities (52%), or reported other symptoms suggestive of insomnia or excessive daytime sleepiness. More frequent insomnia problems were reported among women who reported nocturnal sleep longer than the mode of 7 hours, as well as among women who reported very short sleep. Age, ethnicity, hormone replacement therapy, employment, marital status, diet, and season explained remarkably little of the variance in sleep duration or insomnia complaints; however, black women reported sleeping 0.45 hours on average less than whites, with the other minorities being intermediate between these groups. CONCLUSIONS: The results suggest that simple abbreviation of sleep and demographic factors may be less important in the sleep complaints of postmenopausal women than other possible factors. Cognitive-behavioral processes, depression, and obesity with apnea may be among the causes.


A new anglerfish from eastern Australia and New Caledonia (Lophiiformes: Chaunacidae: Chaunacops), with new data and submersible observation of Chaunacops melanostomus.
A new deep-sea anglerfish of the genus Chaunacops is described based on three specimens collected from eastern Australia and New Caledonia. It differs from its congeners in having fine dermal spinules, mixed with simple and bifurcate ones, densely covering the body, four neuromasts on the pectoral series of the lateral line and a combination of other characteristics. Data for Chaunacops melanostomus based on 31 specimens newly collected from Western Australia are provided. An underwater observation of C. melanostomus made by a remotely operated vehicle is also provided.


Assessment of genetically modified soybean MON 87705 × MON 87708 × MON 89788, for food and feed uses, under Regulation (EC) No 1829/2003 (application EFSA-GMO-NL-2015-126).
Soybean MON 87705 × MON 87708 × MON 89788 (three-event stack soybean) was produced by conventional crossing to combine three single soybean events: MON 87705, MON 87708 and MON 89788. This combination is intended to alter the fatty acid profile in the seed (in particular increasing the levels of oleic acid) and tolerance to glyphosate-based and dicamba herbicides. The Genetically Modified Organisms Panel previously assessed the three single soybean events and did not identify safety concerns. No new data on the single soybean events, leading to modification of the original conclusions on their safety have been identified. The molecular characterisation, comparative analysis (agronomic, phenotypic and compositional characteristics) and the outcome of the toxicological, allergenicity and nutritional assessment indicate that the combination of the single soybean events and of the newly expressed proteins in the three-event stack soybean does not give rise to food and feed safety and nutritional concerns. In the case of accidental release of viable three-event stack soybean seeds into the environment, this would not raise environmental safety concerns. The post-market environmental monitoring plan and the reporting intervals are in line with the intended uses of soybean MON 87705 × MON 87708 × MON 89788. Considering the altered fatty acid profile of the three-event stack soybean, a proposal for post-market monitoring needs to be provided by the applicant. The GMO Panel notes that in the context of this application EFSA-GMO-NL-2015-126 the applicant did not provide a 90-day study on MON 87705 soybean in line with the applicable legal requirements. Therefore, the GMO Panel is not in the position to finalise the risk assessment of soybean MON 87705 × MON 87708 × MON 89788 under the current regulatory frame.


Glutathione and catalase suppress TGFbeta-induced cataract-related changes in cultured rat lenses and lens epithelial explants.
The damaging effects of oxidative stress and transforming growth factor-beta (TGFbeta)-induced transdifferentiation of lens epithelial cells have both been implicated independently in the etiology of cataract. The aim of this study was to investigate whether the presence of antioxidant systems in the lens influences the ability of lens epithelial cells to respond to TGFbeta. Whole lenses from young rats were cultured with or without TGFbeta in the presence or absence of reduced glutathione (GSH). Lens epithelial explants from weanling rats were used to investigate the effects of GSH and catalase on TGFbeta-induced cataract-related changes. Lenses were monitored for opacification for three to four days, photographed, and then processed for routine histology. Explants were assessed by phase contrast microscopy, enzyme-linked immunosorbent assay (ELISA) of alpha-smooth muscle actin (alphaSMA), and/or immunolocalization of alphaSMA and Pax6, markers for transdifferentiation and normal lens epithelial phenotype, respectively. In cultured lenses, GSH strongly suppressed TGFbeta-induced opacification and subcapsular plaque formation. In explants, both GSH and catalase suppressed changes typically associated with TGFbeta-induced transdifferentiation including wrinkling of the lens capsule, cell-surface blebbing, apoptotic cell loss, induction of alphaSMA, and loss of Pax6 expression. This study suggests that antioxidant systems present in the normal lens, which protect the epithelium against the damaging effects of reactive oxygen species, may also serve to protect it against the potentially cataractogenic effects of TGFbeta. Taken together with other recent studies, it also raises the possibility that TGFbeta may induce cataract-related changes in lens epithelial cells via release of hydrogen peroxide.


Thyroid hormone promotes remodeling of coronary resistance vessels.
Low thyroid hormone (TH) function has been linked to impaired coronary blood flow, reduced density of small arterioles, and heart failure. Nonetheless, little is known about the mechanisms by which THs regulate coronary microvascular remodeling. The current study examined the initial cellular events associated with coronary remodeling induced by triiodothyronine (T3) in hypothyroid rats. Rats with established hypothyroidism, eight weeks after surgical thyroidectomy (TX), were treated with T3 for 36 or 72 hours. The early effects of T3 treatment on coronary microvasculature were examined morphometrically. Gene expression changes in the heart were assessed by quantitative PCR Array. Hypothyroidism resulted in arteriolar atrophy in the left ventricle. T3 treatment rapidly induced small arteriolar muscularization and, within 72 hours, restored arteriolar density to control levels. Total length of the capillary network was not affected by TX or T3 treatment. T3 treatment resulted in the coordinate regulation of Angiopoietin 1 and 2 expression. The response of Angiopoietins was consistent with vessel enlargement. In addition to the well known effects of THs on vasoreactivity, these results suggest that THs may affect function of small resistance arteries by phenotypic remodeling of vascular smooth muscle cells (VSMC).


Stereoselective synthesis of unnatural (2S,3S)-6-hydroxy-4-sphingenine-containing sphingolipids.
6-Hydroxy-(4E)-sphingenine-containing sphingolipids are found in mammalian and bacterial membranes and have multiple intra- and intercellular functions. Most sphingolipids contain a (2S,3R)-2-amino-1,3-diol core structure, but only limited examples of unnatural (2S,3S)-2-amino-1,3-diol derivates have so far been reported. Using an underexplored hydrozirconation-transmetalation reaction and an unusual three-step-one-pot deprotection sequence, we were able to synthesize several unnatural (2S,3S)-6-hydroxy-(4E)-sphingenine-containing sphingolipids in only three (protected) or four (deprotected) consecutive steps, respectively, including a fluoresence-labeled derivative suitable for future biological studies.


Upregulation of Serum miR-10b Is Associated with Poor Prognosis in Patients with Melanoma.
Aberrant expression of microRNAs (miRNAs) are believed to play a central role in the initiation and development of cancer. The aim of our study was to determine the clinical significance of serum miR-10b in melanoma. A total of 85 and 30 serum samples were obtained from patients with melanoma and healthy volunteers respectively. qRT-PCR was performed to evaluate the expression level of miR-10b in the melanoma cell lines and the serum samples from the participants. Then the clinical significance of serum miR-10b was further determined. Our results showed that the expression level of miR-10b was significantly increased in metastasis melanoma cells and melanoma patients compared to their respective controls. In addition, serum miR-10b expression level was able to discriminate melanoma patients from healthy volunteers as well differentiate melanoma patients at different clinical stage with high accuracy. Moreover, upregulation of serum miR-10b was positively associated with enhanced lymph node metastasis, advanced clinical stage and a shortened survival rate. Finally serum miR-10b was an independent prognostic factor for melanoma. Collectively, our study suggests that serum miR-10b level is upregulated in melanoma and associated with poor prognosis. It may be used as a potential prognostic biomarker for melanoma.


Strain specific stress-modulating effects of candidate probiotics: A systematic screening in a mouse model of chronic restraint stress.
Changes in the gut microbiota have been implicated in mood and cognition. In rodents, supplementation with certain bacteria have been shown to alleviate adverse effects of stress on gut microbiota composition and behaviour, but little is known of how the performance of different strains compare to each other. We took a systematic approach to test the efficacy of twelve candidate probiotic strains from ten species/sub-species of Bifidobacterium and Lactobacillus on behaviours and neuroendocrine responses of chronically stressed mice. The strains were tested in four screening experiments with non-stressed and chronically stressed vehicle groups. The three most efficacious strains were re-tested to validate the results. Mice were administered a daily oral gavage containing either 1 × 109 colony forming units (CFU) of selected candidate probiotic or saline solution for one week prior to and for three weeks during daily chronic restraint stress. Behavioural tests including the elevated plus maze, open field, novel object recognition, and forced swim test were applied during week five. Corticosterone and adrenocorticotropic hormone (ACTH) were analysed to measure the neuroendocrine response to stress. Plasma and tissue samples were collected for biomarker analyses. Of the twelve candidate probiotics, Lactobacillus paracasei Lpc-37, Lactobacillus plantarum LP12407, Lactobacillus plantarum LP12418 and Lactobacillus plantarum LP12151 prevented stress-associated anxiety and depression-related behaviours from developing compared with chronically stressed vehicle mice. In addition, Lpc-37 improved cognition. This systematic screening indicates species- and strain-dependent effects on behavioural outcomes related to stress and further suggests that strains differ from each other in their effects on potential mechanistic outcomes.


Geospatial resources for supporting data standards, guidance and best practice in health informatics.
The 1980s marked the occasion when Geographical Information System (GIS) technology was broadly introduced into the geo-spatial community through the establishment of a strong GIS industry. This technology quickly disseminated across many countries, and has now become established as an important research, planning and commercial tool for a wider community that includes organisations in the public and private health sectors.The broad acceptance of GIS technology and the nature of its functionality have meant that numerous datasets have been created over the past three decades. Most of these datasets have been created independently, and without any structured documentation systems in place. However, search and retrieval systems can only work if there is a mechanism for datasets existence to be discovered and this is where proper metadata creation and management can greatly help.This situation must be addressed through support mechanisms such as Web-based portal technologies, metadata editor tools, automation, metadata standards and guidelines and collaborative efforts with relevant individuals and organisations. Engagement with data developers or administrators should also include a strategy of identifying the benefits associated with metadata creation and publication. The establishment of numerous Spatial Data Infrastructures (SDIs), and other Internet resources, is a testament to the recognition of the importance of supporting good data management and sharing practices across the geographic information community. These resources extend to health informatics in support of research, public services and teaching and learning.This paper identifies many of these resources available to the UK academic health informatics community. It also reveals the reluctance of many spatial data creators across the wider UK academic community to use these resources to create and publish metadata, or deposit their data in repositories for sharing.The Go-Geo! service is introduced as an SDI developed to provide UK academia with the necessary resources to address the concerns surrounding metadata creation and data sharing. The Go-Geo! portal, Geodoc metadata editor tool, ShareGeo spatial data repository, and a range of other support resources, are described in detail. This paper describes a variety of resources available for the health research and public health sector to use for managing and sharing their data. The Go-Geo! service is one resource which offers an SDI for the eclectic range of disciplines using GIS in UK academia, including health informatics.The benefits of data management and sharing are immense, and in these times of cost restraints, these resources can be seen as solutions to find cost savings which can be reinvested in more research.


Significant redistribution of Ce 4d oscillator strength observed in photoionization of endohedral Ce@C82+ ions.
Mass-selected beams of atomic Ceq+ ions (q = 2, 3, 4), of C82+ and of endohedral Ce@C82+ ions were employed to study photoionization of free and encaged cerium atoms. The Ce 4d inner-shell contributions to single and double ionization of the endohedral Ce@C82+ fullerene have been extracted from the data and compared with expectations based on theory and the experiments with atomic Ce ions. Dramatic reduction and redistribution of the ionization contributions to 4d photoabsorption is observed. More than half of the Ce 4d oscillator strength appears to be diverted to the additional decay channels opened by the fullerene cage surrounding the Ce atom.


Gene expression profiling reveals different pathways related to Abl and other genes that cooperate with c-Myc in a model of plasma cell neoplasia.
To elucidate the genes involved in the neoplastic transformation of B cells, global gene expression profiles were generated using Affymetrix U74Av2 microarrays, containing 12,488 genes, for four different groups of mouse B-cell lymphomas and six subtypes of pristane-induced mouse plasma cell tumors, three of which developed much earlier than the others. Unsupervised hierarchical cluster analysis exhibited two main sub-clusters of samples: a B-cell lymphoma cluster and a plasma cell tumor cluster with subclusters reflecting mechanism of induction. This report represents the first step in using global gene expression to investigate molecular signatures related to the role of cooperating oncogenes in a model of Myc-induced carcinogenesis. Within a single subgroup, e.g., ABPCs, plasma cell tumors that contained typical T(12;15) chromosomal translocations did not display gene expression patterns distinct from those with variant T(6;15) translocations, in which the breakpoint was in the Pvt-1 locus, 230 kb 3' of c-Myc, suggesting that c-Myc activation was the initiating factor in both. When integrated with previously published Affymetrix array data from human multiple myelomas, the IL-6-transgenic subset of mouse plasma cell tumors clustered more closely with MM1 subsets of human myelomas, slow-appearing plasma cell tumors clustered together with MM2, while plasma cell tumors accelerated by v-Abl clustered with the more aggressive MM3-MM4 myeloma subsets. Slow-appearing plasma cell tumors expressed Socs1 and Socs2 but v-Abl-accelerated plasma cell tumors expressed 4-5 times as much. Both v-Abl-accelerated and non-v-Abl-associated tumors exhibited phosphorylated STAT 1 and 3, but only v-Abl-accelerated plasma cell tumors lost viability and STAT 1 and 3 phosphorylation when cultured in the presence of the v-Abl kinase inhibitor, STI-571. These data suggest that the Jak/Stat pathway was critical in the transformation acceleration by v-Abl and that v-Abl activity remained essential throughout the life of the tumors, not just in their acceleration. A different pathway appears to predominate in the more slowly arising plasma cell tumors. Gene expression profiling differentiates not only B-cell lymphomas from plasma cell tumors but also distinguishes slow from accelerated plasma cell tumors. These data and those obtained from the sensitivity of v-Abl-accelerated plasma cell tumors and their phosphorylated STAT proteins indicate that these similar tumors utilize different signaling pathways but share a common initiating genetic lesion, a c-Myc-activating chromosome translocation.


Allogeneic hematopoietic stem cell transplantation in myelofibrosis: the 20-year experience of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO).
Allogeneic stem cell transplantation is a potentially curative treatment for myelofibrosis, although its use is limited by a high rate of transplant-related mortality. In this study, we evaluated the outcome of patients with myelofibrosis who underwent allogeneic stem cell transplantation, and the impact of prognostic factors. One hundred patients were transplanted in 26 Italian centers between 1986 and 2006. We analyzed the influence of the patients' characteristics and the clinical features of their disease before stem cell transplantation and of transplant procedures on transplant-related mortality, overall survival, and relapse-free survival by means of univariate and multivariate analyses. The median age of the patients at the time of stem cell transplantation was 49 years (range, 21-68) and 90% of them had an intermediate or high Dupriez score. Forty-eight percent received a myeloablative conditioning regimen and 78% received stem cells from matched sibling donors. The cumulative incidence of engraftment at day 90 after transplant was 87% (95% CI, 0.87-0.97). The cumulative 1-year and 3-year incidences of transplant-related mortality were 35% and 43%, respectively. The estimated 3-year overall and relapse-free survival rates after stem cell transplantation were 42% and 35%, respectively. In multivariate analysis, negative predictors of transplant-related mortality were year of stem cell transplantation before 1995, unrelated donor, and a long interval between diagnosis and transplantation. There was a trend towards longer overall and relapse-free survival in patients receiving peripheral blood stem cells rather than bone marrow as the source of their graft (p=0.070 and p=0.077, respectively). The intensity of the conditioning regimen (myeloablative versus reduced intensity regimens) did not significantly influence the outcome. We conclude that the outcome of myelofibrosis patients who underwent allogeneic stem cell transplantation significantly improved after 1996 due to the reduction in transplant-related mortality. We observed that a reduction in transplant-related mortality was associated with the choice of a matched sibling donor, whereas longer overall survival was associated with the use of peripheral blood as the source of stem cells.


Japanese encephalitis vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP).
This report updates the 1993 recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the prevention of Japanese encephalitis (JE) among travelers (CDC. Inactivated Japanese encephalitis virus vaccine: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 1993;42[No. RR-1]). This report summarizes the epidemiology of JE, describes the two JE vaccines that are licensed in the United States, and provides recommendations for their use among travelers and laboratory workers. JE virus (JEV), a mosquito-borne flavivirus, is the most common vaccine-preventable cause of encephalitis in Asia. JE occurs throughout most of Asia and parts of the western Pacific. Among an estimated 35,000-50,000 annual cases, 20%-30% of patients die, and 30%-50% of survivors have neurologic or psychiatric sequelae. No treatment exists. For most travelers to Asia, the risk for JE is very low but varies on the basis of destination, duration, season, and activities. JE vaccine is recommended for travelers who plan to spend a month or longer in endemic areas during the JEV transmission season and for laboratory workers with a potential for exposure to infectious JEV. JE vaccine should be considered for 1) short-term (<1 month) travelers to endemic areas during the JEV transmission season if they plan to travel outside of an urban area and will have an increased risk for JEV exposure; 2) travelers to an area with an ongoing JE outbreak; and 3) travelers to endemic areas who are uncertain of specific destinations, activities, or duration of travel. JE vaccine is not recommended for short-term travelers whose visit will be restricted to urban areas or times outside of a well-defined JEV transmission season. Two JE vaccines are licensed in the United States. An inactivated mouse brain--derived JE vaccine (JE-VAX [JE-MB]) has been licensed since 1992 to prevent JE in persons aged >or=1 year traveling to JE-endemic countries. Supplies of this vaccine are limited because production has ceased. In March 2009, an inactivated Vero cell culture-derived vaccine (IXIARO [JE-VC]) was licensed for use in persons aged >or=17 years. JE-MB is the only JE vaccine available for use in children aged 1-16 years, and remaining supplies will be reserved for use in this group.


Soft drink prices, sales, body mass index and diabetes: Evidence from a panel of low-, middle- and high-income countries.
We take advantage of four different cross-country datasets containing data on 78 countries for the period 1999-2014, in order to assess the relationship of carbonated soft drinks' sales, as well as their prices, with body mass index (BMI), overweight, obesity and diabetes. Using an ecological study design and multivariate regression longitudinal estimation approaches, we find that carbonated soft drink sales were significantly positively related to BMI, overweight and obesity - but only in the low and lower-middle income countries. This finding was robust to a number of sensitivity and falsification checks. In this sub-sample, an increase in per capita soft drink sales by 1 litre per year was related to an increase of BMI by about 0.009 kg/m2 (p < 0.1).. This is a small effect, implying that halving annual consumption per capita in this group of countries would result in a drop of BMI by only about 0.03 kg/m2. Although soft drink prices were negatively related to weight-related outcomes in the sample of higher middle income and high income countries, this finding was not robust to falsification checks. The results thus suggest that sales restrictions to steer consumers away from soft drinks could indeed have a beneficial health effects in poorer countries, although the effect magnitude appears to be very small. However, given potential limitations of using ecological research design, results from individual level studies would be required to further ascertain the role of soft drink sales and prices in obesity and diabetes.


[Recognition of three different imagined movement of the right foot based on functional near-infrared spectroscopy].
Brain-computer interface (BCI) based on functional near-infrared spectroscopy (fNIRS) is a new-type human-computer interaction technique. To explore the separability of fNIRS signals in different motor imageries on the single limb, the study measured the fNIRS signals of 15 subjects (amateur football fans) during three different motor imageries of the right foot (passing, stopping and shooting). And the correlation coefficient of the HbO signal during different motor imageries was extracted as features for the input of a three-classification model based on support vector machines. The results found that the classification accuracy of the three motor imageries of the right foot was 78.89%±6.161%. The classification accuracy of the two-classification of motor imageries of the right foot, that is, passing and stopping, passing and shooting, and stopping and shooting was 85.17%±4.768%, 82.33%±6.011%, and 89.33%±6.713%, respectively. The results demonstrate that the fNIRS of different motor imageries of the single limb is separable, which is expected to add new control commands to fNIRS-BCI and also provide a new option for rehabilitation training and control peripherals for unilateral stroke patients. Besides, the study also confirms that the correlation coefficient can be used as an effective feature to classify different motor imageries.


Temporal relationship between hepatitis B virus enhancer II/basal core promoter sequence variation and risk of hepatocellular carcinoma.
To investigate the temporal relationship between sequence variation in the enhancer II (EnhII), basal core promoter (BCP), and precore regions of hepatitis B virus (HBV) and the risk of hepatocellular carcinoma (HCC), we conducted a nested case-control study within a cohort of 4841 male HBV carriers who were recruited during the period 1988-1992. The HBV DNA sequence was determined in baseline blood samples taken from 132 incident cases and 204 controls. Base exchanges during follow-up in 71 cases were compared with 81 controls with samples taken during a similar length of follow-up. Nine single nucleotide polymorphisms in the EnhII/BCP regions (six of which were genotype C HBV related) were associated with subsequent risk of HCC. The strength of these associations decreased as the lag time between baseline measurement and diagnosis increased over 3 years. However, an increased disease risk in subjects with BCP double variants (mostly T1762/A1764) or genotype C HBV-related variants was evident 9 years or more before diagnosis. The BCP double variants (odds ratio, 1.92 (95% confidence interval, 1.14 to 3.25)) were statistically significantly associated with HCC risk even after adjusting for alanine aminotransferase levels, antibodies against HBV e antigen, HBV genotype, HBV viral load, and other sequence variants. Longitudinal analysis indicated that the increased HCC risks for at-risk sequence variants were attributable to the persistence of these variants. HCC risk is associated with sequence variation in the EnhII/BCP regions of HBV, and persistence of at-risk sequence variants is critical for HCC development.


The impact of nanomaterial characteristics on inhalation toxicity.
During the last few decades, nanotechnology has evolved into a success story, apparent from a steadily increasing number of scientific publications as well as a large number of applications based on engineered nanomaterials (ENMs). Its widespread uses suggest a high relevance for consumers, workers and the environment, hence justifying intensive investigations into ENM-related adverse effects as a prerequisite for nano-specific regulations. In particular, the inhalation of airborne ENMs, being assumed to represent the most hazardous type of human exposure to these kinds of particles, needs to be scrutinized. Due to an increased awareness of possible health effects, which have already been seen in the case of ultrafine particles (UFPs), research and regulatory measures have set in to identify and address toxic implications following their almost ubiquitous occurrence. Although ENM properties differ from those of the respective bulk materials, the available assessment protocols are often designed for the latter. Despite the large benefit ensuing from the application of nanotechnology, many issues related to ENM behavior and adverse effects are not fully understood or should be examined anew. The traditional hypothesis that ENMs exhibit different or additional hazards due to their "nano" size has been challenged in recent years and ENM categorization according to their properties and toxicity mechanisms has been proposed instead. This review summarizes the toxicological effects of inhaled ENMs identified to date, elucidating the modes of action which provoke different mechanisms in the respiratory tract and their resulting effects. By linking particular mechanisms and adverse effects to ENM properties, grouping of ENMs based on toxicity-related properties is supposed to facilitate toxicological risk assessment. As intensive studies are still required to identify these "ENM classes", the need for alternatives to animal studies is evident and advances in cell-based test systems for pulmonary research are presented here. We hope to encourage the ongoing discussion about ENM risks and to advocate the further development and practice of suitable testing and grouping methods.


Unlocking reflective practice for nurses: innovations in working with master of nursing students in Hong Kong.
Being reflective is well established as an important conduit of practice development, a desirable tertiary graduate quality and a core competency of health professional membership. By assisting students to be more effective in their ability to reflect, they are better able to formulate strategies to manage issues experienced within a professional context, which ultimately assists them to be better service providers. However, some students are challenged by the practice of reflection and these challenges are even more notable for international students. This paper presents a teaching initiative that focused specifically on enhancing the capacity of an international cohort of nursing students, to engage in reflective practice. The initiative centered on an evaluation of a reflective practice core subject, which was taught in a Master of Nursing programme delivered in Hong Kong. A learning-centered framework was used to evaluate the subject and identify innovative strategies that would better assist international students to develop reflective practices. The outcomes of curriculum and teaching analysis and proposed changes and innovations in teaching practice to support international students are presented and discussed.


Multiple subelements within the polyomavirus enhancer function synergistically to activate DNA replication.
The polyomavirus origin for DNA replication comprises at least two essential, but functionally distinct, cis-acting components. One of these, the origin core, is required only for DNA replication. It includes binding sites for large T antigen and the origin of bidirectional DNA replication. The other component is required for both transcription and DNA replication and is represented by two functionally redundant regions, alpha and beta, which are elements of the polyomavirus enhancer. Whereas either enhancer element will activate DNA replication, both enhancer elements are required to constitute a functional enhancer of transcription. To identify the sequences that make up each enhancer element, we have subjected them separately to in vitro mutagenesis and measured their capacity to activate replication in cis of the origin core in MOP-8 cells, which provide all trans-acting replicative functions including large T antigen. The results reveal that the beta enhancer element is composed of three subelements, two auxiliary subelements, and a core subelement. The core subelement independently activated DNA replication, albeit poorly. The auxiliary subelements, which were inactive on their own, acted synergistically with the core subelement to increase its activity. Interestingly, dimers of the beta core subelement functioned as well as the combination of a beta auxiliary subelement and a core subelement, suggesting that the subelements are functionally equivalent. The alpha enhancer element is organized similarly; it too comprises an auxiliary subelement and a core subelement. These results lead us to suggest that the polyomavirus enhancer comprises two levels of organization; two or more enhancer elements form an enhancer, and two or more subelements make up an enhancer element. The subelements share few sequences and serve as binding sites for distinct cellular factors. It appears, therefore, that a number of different cellular proteins function cooperatively to activate polyomavirus DNA replication by a common mechanism.


Improving wastewater management using free nitrous acid (FNA).
Free nitrous acid (FNA), the protonated form of nitrite, has historically been an unwanted substance in wastewater systems due to its inhibition on a wide range of microorganisms. However, in recent years, advanced understanding of FNA inhibitory and biocidal effects on microorganisms has led to the development of a series of FNA-based applications that improve wastewater management practices. FNA has been used in sewer systems to control sewer corrosion and odor; in wastewater treatment to achieve carbon and energy efficient nitrogen removal; in sludge management to improve the sludge reduction and energy recovery; in membrane systems to address membrane fouling; and in wastewater algae systems to facilitate algae harvesting. This paper aims to comprehensively and critically review the current status of FNA-based applications in improving wastewater management. The underlying mechanisms of FNA inhibitory and biocidal effects are also reviewed and discussed. Knowledge gaps and current limitations of the FNA-based applications are identified; and perspectives on the development of FNA-based applications are discussed. We conclude that the FNA-based technologies have great potential for enhancing the performance of wastewater systems; however, further development and demonstration at larger scales are still required for their wider applications.


A double-blind placebo-controlled study of an infusion of lexipafant (Platelet-activating factor receptor antagonist) in patients with severe sepsis.
Platelet-activating factor (PAF) is a potent endogenous proinflammatory mediator implicated in the pathogenesis of septic shock. A double-blind randomized placebo-controlled trial of an intravenous PAF receptor antagonist (lexipafant) was conducted with 131 adult Thai patients with suspected severe sepsis (66 of whom had positive blood cultures). Detailed serial clinical, biochemical, and cytokine measurements were performed. Lexipafant treatment was well tolerated. The 28-day mortality in the lexipafant group (61.4%) was similar to that in the placebo group (62.6%). There was also no evidence that lexipafant affected clinical or biochemical measures of disease severity or the profile of sequentially measured plasma cytokine levels. PAF may not have an important role in the pathogenesis of severe sepsis.


Iron deficiency: global prevalence and consequences.
Iron deficiency is considered to be one of most prevalent forms of malnutrition, yet there has been a lack of consensus about the nature and magnitude of the health consequences of iron deficiency in populations. This paper presents new estimates of the public health importance of iron-deficiency anemia (IDA), which were made as part of the Global Burden of Disease (GBD) 2000 project. Iron deficiency is considered to contribute to death and disability as a risk factor for maternal and perinatal mortality, and also through its direct contributions to cognitive impairment, decreased work productivity, and death from severe anemia. Based on meta-analysis of observational studies, mortality risk estimates for maternal and perinatal mortality are calculated as the decreased risk in mortality for each 1 g/dl increase in mean pregnancy hemoglobin concentration. On average, globally, 50% of the anemia is assumed to be attributable to iron deficiency. Globally, iron deficiency ranks number 9 among 26 risk factors included in the GBD 2000, and accounts for 841,000 deaths and 35,057,000 disability-adjusted life years lost. Africa and parts of Asia bear 71% of the global mortality burden and 65% of the disability-adjusted life years lost, whereas North America bears 1.4% of the global burden. There is an urgent need to develop effective and sustainable interventions to control iron-deficiency anemia. This will likely not be achieved without substantial involvement of the private sector.