Endovascular treatment of side wall aneurysms using a liquid embolic agent: a US single-center prospective trial.
Onyx HD-500 is a liquid embolic agent consisting of ethylene vinyl alcohol copolymer dissolved in dimethylsulfoxide and mixed with tantalum. This viscous embolic agent was designed to treat intracranial side wall aneurysms, but there have been no prospective published series from the United States. From this early experience, we developed several protocol revisions, technical details, and clinical pearls that have not been published for liquid embolic embolization of aneurysms. We present our single-center prospective series of patients treated with Onyx HD-500 from a multicenter, randomized, controlled trial. Thirteen patients received Onyx HD-500, and their ages ranged from 43 to 81 years. Twelve patients had aneurysms on the internal carotid artery, and 1 patient had an aneurysm the vertebral artery. Every patient had an immediate postangiographic result with 90% or more occlusion by an independent core laboratory assessment. In 1 patient, the Onyx HD-500 injection was aborted, and the aneurysm was embolized with coils. Eleven of 13 patients (85%) underwent 6-month follow-up angiography that demonstrated persistent durable occlusion with no recanalization. There was 1 complication (8%) and no deaths. This is the only prospective series of intracranial aneurysms treated with Onyx HD-500 in the United States. This is also the first publication that describes detailed procedure techniques, recommended protocol revisions, lessons learned from early complications, clinical pearls, and advantages and disadvantages of liquid embolic embolization of aneurysms.


Obsessive-compulsive beliefs and treatment outcome.
Of 49 compulsive ritualizers one-third perceived their obsessive thoughts as a rational and felt that their rituals warded off some unwanted or feared event (the content of their obsessions). The more bizarre the obsessive belief the more strongly it was defended and 12% of cases made no attempt to resist the urge to ritualize. Neither fixity of belief nor resistance to compulsive urges were related to duration of illness. Patients with bizarre and fixed obsessive beliefs responded as well to treatment (all but three received exposure), as did patients whose obsessions were less bizarre and recognized as senseless. There was no difference in outcome between patients who initially found it hard to control their obsessions or never resisted the urge to ritualize and those who initially could control obsessions or resist rituals. One year after starting treatment, patients whose obsessions and compulsions had improved with treatment recognized their irrationality more readily and controlled their compulsive urges more easily. Beliefs appeared to normalize as a function of habituation.


A five year physiological case study of an Olympic runner.
To study physiological changes caused by long term endurance training in a world class female distance runner, and to compare these changes with alterations in 3000 m running performance. The subject underwent regular physiological assessment during the period 1991-1995. Physiological measures made included body composition, maximal oxygen uptake (VO2MAX), running economy, and lactate threshold. In addition, the running speed at VO2MAX was estimated. Test protocols, laboratory equipment, and laboratory techniques used were the same for each test session. The 3000 m race performance improved by 8% from 1991 to 1993 after which it stabilised. In contrast, VO2MAX fell from 1991 (73 ml/kg/min) to 1993 (66 ml/kg/min). Submaximal physiological variables such as lactate threshold (from 15.0 to 18.0 km/h) and running economy (from 53 ml/kg/min to 48 ml/kg/min at 16.0 km/h) improved over the course of the study. Despite no increase in VO2MAX, the reduction in the oxygen cost of submaximal running caused the estimated running speed at VO2MAX to increase from 19.0 km/h in 1991 to 20.4 km/h in 1995. Improvement in 3000 m running performance was not caused by an increase in VO2MAX. Rather, the extensive training programme adopted, together perhaps with physical maturation, resulted in improvements in submaximal fitness factors such as running economy and lactate threshold. These adaptations improved the running speed estimated to be associated with VO2MAX, and resulted in improved 3000 m running performance.


A Minimalist Approach to the Design of Complexity-Enriched Bioactive Small Molecules: Discovery of Phenanthrenoid Mimics as Antiproliferative Agents.
Over the last decades, much effort has been devoted to the design of the "ideal" library for screening, the most promising strategies being those which draw inspiration from biogenic compounds, as the aim is to add biological relevance to such libraries. On the other hand, there is a growing understanding of the role that molecular complexity plays in the discovery of new bioactive small molecules. Nevertheless, the introduction of molecular complexity must be balanced with synthetic accessibility. In this work, we show that both concepts can be efficiently merged-in a minimalist way-by using very simple guidelines during the design process along with the application of multicomponent reactions as key steps in the synthetic process. Natural phenanthrenoids, a class of plant aromatic metabolites, served as inspiration for the synthesis of a library in which complexity-enhancing features were introduced in few steps using multicomponent reactions. These resulting chemical entities were not only more complex than the parent natural products, but also interrogated an alternative region of the chemical space, which led to an outstanding hit rate in an antiproliferative assay: four out of twenty-six compounds showed in vitro activity, one of them being more potent than the clinically useful drug 5-fluorouracil.


Magnetic Anomalies over Iceland.
An aeromagnetic survey of Iceland reveals broad anomalies of large amplitude over zones of recent volcanic activity. The source of the anomalies is ascribed to large masses of basalt that have been coherently remagnetized by intrusive heating. A simple correlation of the Icelandic anomalies with those of the ocean floor therefore appears unjustified.


First Report of Fire Blight Caused by Erwinia amylovora on Pyracantha coccinea in Bulgaria.
During late May and June of 2003, a fire blight epidemic occurred in southcentral Bulgaria on earlier reported hosts such as apple, pear, quince, and hawthorn (1). A new host was found when fire blight was also observed in mid-June on Pyracantha coccinea grown in the Plovdiv Region. Symptoms were necrotic flowers, shoots, petioles, and the presence of sticky ooze droplets mainly on the shoots. Isolations made from blighted Pyracantha coccinea flowers and shoots onto King's medium B (2 days at 25 to 26°C) yielded whitish, glistening, round bacterial colonies. Infiltration of the suspensions of three of the isolates into tobacco leaves resulted in a typical hypersensitive reaction. When Pyracantha coccinea and Cotoneaster sp. shoots were inoculated with these three isolates, typical fire blight symptoms were obtained. The pathogen was reisolated 2 weeks after inoculation from necrotic tissues (15 to 20 mm above and below the inoculation site), thereby fulfilling the Koch's postulates. No symptoms and bacteria were found within any of the shoots from the same plant species injected with sterile water. The identity of the isolates was also determined by conducting nested polymerase chain reaction (PCR) (2) and target-specific PCR (23S rDNA) (3). On the basis of the symptoms, cultural characteristics, and positive results in pathogenicity and PCR tests, the isolates were considered to be Erwinia amylovora. To our knowledge, this is the first report of fire blight on Pyracantha coccinea in Bulgaria. References: (1) S. G. Bobev et al. Plant Dis. 82:1283, 1998. (2) P. Llop et al. Appl. Environ. Microbiol. 66:2071, 2000. (3) M. Maes et al. Plant Pathol. 45:1139, 1996.


Microarray analysis and scale-free gene networks identify candidate regulators in drought-stressed roots of loblolly pine (P. taeda L.).
Global transcriptional analysis of loblolly pine (Pinus taeda L.) is challenging due to limited molecular tools. PtGen2, a 26,496 feature cDNA microarray, was fabricated and used to assess drought-induced gene expression in loblolly pine propagule roots. Statistical analysis of differential expression and weighted gene correlation network analysis were used to identify drought-responsive genes and further characterize the molecular basis of drought tolerance in loblolly pine. Microarrays were used to interrogate root cDNA populations obtained from 12 genotype × treatment combinations (four genotypes, three watering regimes). Comparison of drought-stressed roots with roots from the control treatment identified 2445 genes displaying at least a 1.5-fold expression difference (false discovery rate = 0.01). Genes commonly associated with drought response in pine and other plant species, as well as a number of abiotic and biotic stress-related genes, were up-regulated in drought-stressed roots. Only 76 genes were identified as differentially expressed in drought-recovered roots, indicating that the transcript population can return to the pre-drought state within 48 hours. Gene correlation analysis predicts a scale-free network topology and identifies eleven co-expression modules that ranged in size from 34 to 938 members. Network topological parameters identified a number of central nodes (hubs) including those with significant homology (E-values ≤ 2 × 10-30) to 9-cis-epoxycarotenoid dioxygenase, zeatin O-glucosyltransferase, and ABA-responsive protein. Identified hubs also include genes that have been associated previously with osmotic stress, phytohormones, enzymes that detoxify reactive oxygen species, and several genes of unknown function. PtGen2 was used to evaluate transcriptome responses in loblolly pine and was leveraged to identify 2445 differentially expressed genes responding to severe drought stress in roots. Many of the genes identified are known to be up-regulated in response to osmotic stress in pine and other plant species and encode proteins involved in both signal transduction and stress tolerance. Gene expression levels returned to control values within a 48-hour recovery period in all but 76 transcripts. Correlation network analysis indicates a scale-free network topology for the pine root transcriptome and identifies central nodes that may serve as drivers of drought-responsive transcriptome dynamics in the roots of loblolly pine.


Formal linguistics as a cue to demographic history.
Beyond its theoretical success, the development of molecular genetics has brought about the possibility of extraordinary progress in the study of classification and in the inference of the evolutionary history of many species and populations. A major step forward was represented by the availability of extremely large sets of molecular data suited to quantitative and computational treatments. In this paper, we argue that even in cognitive sciences, purely theoretical progress in a discipline such as linguistics may have analogous impact. Thus, exactly on the model of molecular biology, we propose to unify two traditionally unrelated lines of linguistic investigation: 1) the formal study of syntactic variation (parameter theory) in the biolinguistic program; 2) the reconstruction of relatedness among languages (phylogenetic taxonomy). The results of our linguistic analysis have thus been plotted against data from population genetics and the correlations have turned out to be largely significant: given a non-trivial set of languages/populations, the description of their variation provided by the comparison of systematic parametric analysis and molecular anthropology informatively recapitulates their history and relationships. As a result, we can claim that the reality of some parametric model of the language faculty and language acquisition/transmission (more broadly of generative grammar) receives strong and original support from its historical heuristic power. Then, on these grounds, we can begin testing Darwin's prediction that, when properly generated, the trees of human populations and of their languages should eventually turn out to be significantly parallel.


Application of data fusion techniques and technologies for wearable health monitoring.
Technological advances in sensors and communications have enabled discrete integration into everyday objects, both in the home and about the person. Information gathered by monitoring physiological, behavioural, and social aspects of our lives, can be used to achieve a positive impact on quality of life, health, and well-being. Wearable sensors are at the cusp of becoming truly pervasive, and could be woven into the clothes and accessories that we wear such that they become ubiquitous and transparent. To interpret the complex multidimensional information provided by these sensors, data fusion techniques are employed to provide a meaningful representation of the sensor outputs. This paper is intended to provide a short overview of data fusion techniques and algorithms that can be used to interpret wearable sensor data in the context of health monitoring applications. The application of these techniques are then described in the context of healthcare including activity and ambulatory monitoring, gait analysis, fall detection, and biometric monitoring. A snap-shot of current commercially available sensors is also provided, focusing on their sensing capability, and a commentary on the gaps that need to be bridged to bring research to market.


The K+ channel opener 1-EBIO potentiates residual function of mutant CFTR in rectal biopsies from cystic fibrosis patients.
The identification of strategies to improve mutant CFTR function remains a key priority in the development of new treatments for cystic fibrosis (CF). Previous studies demonstrated that the K⁺ channel opener 1-ethyl-2-benzimidazolone (1-EBIO) potentiates CFTR-mediated Cl⁻ secretion in cultured cells and mouse colon. However, the effects of 1-EBIO on wild-type and mutant CFTR function in native human colonic tissues remain unknown. We studied the effects of 1-EBIO on CFTR-mediated Cl⁻ secretion in rectal biopsies from 47 CF patients carrying a wide spectrum of CFTR mutations and 57 age-matched controls. Rectal tissues were mounted in perfused micro-Ussing chambers and the effects of 1-EBIO were compared in control tissues, CF tissues expressing residual CFTR function and CF tissues with no detectable Cl⁻ secretion. Studies in control tissues demonstrate that 1-EBIO activated CFTR-mediated Cl⁻ secretion in the absence of cAMP-mediated stimulation and potentiated cAMP-induced Cl⁻ secretion by 39.2±6.7% (P<0.001) via activation of basolateral Ca²⁺-activated and clotrimazole-sensitive KCNN4 K⁺ channels. In CF specimens, 1-EBIO potentiated cAMP-induced Cl⁻ secretion in tissues with residual CFTR function by 44.4±11.5% (P<0.001), but had no effect on tissues lacking CFTR-mediated Cl⁻ conductance. We conclude that 1-EBIO potentiates Cl⁻secretion in native CF tissues expressing CFTR mutants with residual Cl⁻ channel function by activation of basolateral KCNN4 K⁺ channels that increase the driving force for luminal Cl⁻ exit. This mechanism may augment effects of CFTR correctors and potentiators that increase the number and/or activity of mutant CFTR channels at the cell surface and suggests KCNN4 as a therapeutic target for CF.


Practice patterns and perceived impact of clinical nurse specialist roles in Canada: results of a national survey.
Clinical nurse specialists are recognized internationally for providing an advanced level of practice. They positively impact the delivery of healthcare services by using specialty-specific expert knowledge and skills, and integrating competencies as clinicians, educators, researchers, consultants and leaders. Graduate-level education is recommended for the role but many countries do not have formal credentialing mechanisms for clinical nurse specialists. Previous studies have found that clinical nurse specialist roles are poorly understood by stakeholders. Few national studies have examined the utilization of clinical nurse specialists. To identify the practice patterns of clinical nurse specialists in Canada. A descriptive cross-sectional survey. Self-identified clinical nurse specialists in Canada. A 50-item self-report questionnaire was developed, pilot-tested in English and French, and administered to self-identified clinical nurse specialists from April 2011 to August 2011. Data were analyzed using descriptive and inferential statistics and content analysis. The actual number of clinical nurse specialists in Canada remains unknown. The response rate using the number of registry-identified clinical nurse specialists was 33% (804/2431). Of this number, 608 reported working as a clinical nurse specialist. The response rate for graduate-prepared clinical nurse specialists was 60% (471/782). The practice patterns of clinical nurse specialists varied across clinical specialties. Graduate-level education influenced their practice patterns. Few administrative structures and resources were in place to support clinical nurse specialist role development. The lack of title protection resulted in confusion around who identifies themselves as a clinical nurse specialist and consequently made it difficult to determine the number of clinical nurse specialists in Canada. This is the first national survey of clinical nurse specialists in Canada. A clearer understanding of these roles provides stakeholders with much needed information about clinical nurse specialist practice patterns. Such information can inform decisions about policies, education and organizational supports to effectively utilize this role in healthcare systems. This study emphasizes the need to develop standardized educational requirements, consistent role titles and credentialing mechanisms to facilitate the identification and comparison of clinical nurse specialist roles and role outcomes internationally.


Antibiotic resistance pattern of Enterococci isolates from nosocomial infections in a tertiary care hospital in Eastern India.
Resistance to commonly used antibiotics by Enterococci causing nosocomial infections is of concern, which necessitates judicious, responsible and evidence-based use of antibiotics. The present study was conducted to review the prevalence and identify therapeutic options for nosocomial Enterococcal infections in our tertiary care hospital. Isolates identified by morphological and biochemical characteristics were tested for antibiotic susceptibility using Kirby-Bauer method. 153 of 2096 culture positive clinical samples comprised of 101 urine, 30 wound swab/pus, 13 blood and 09 high vaginal swab isolates were identified as Enterococcus faecalis (90.85%), Enterococcus faecium (8.50%) and Enterococcus gallinarum (0.65%). Enterococci accounted for 8.45%, 4.53%, 4.23%, 4.43% of urinary, wound swab or pus, blood, high vaginal swab isolates respectively, causing 7.3% of all nosocomial infections. Significant number of Enterococci isolated from nosocomial urinary tract infection (66.01%) and wound infections (19.6%) were multidrug resistant (MDR). Although all isolates were sensitive to vancomycin and linezolid, resistance to erythromycin (71.24%) and ciprofloxacin (49.67%) was frequently observed. High-level gentamicin resistance was observed in 43.88%, and 61.53% of E. faecalis and E. faecium isolates respectively. Minimal inhibitory concentration of vancomycin of all the isolates were ≤1 μg/ml. 7% of the Enterococcal isolates were MDR strains and vancomycin or linezolid were the only effective antibiotics. A combination of vancomycin and/or linezolid were effective against Enterococci causing nosocomial infections in our tertiary care facility, nevertheless continuous and frequent surveillance for resistance patterns are necessary for judicious and evidence based use of antibiotics.


Friends, Lovers or Nothing: Men and Women Differ in Their Perceptions of Sex Robots and Platonic Love Robots.
Physical and emotional intimacy between humans and robots may become commonplace over the next decades, as technology improves at a rapid rate. This development provides new questions pertaining to how people perceive robots designed for different kinds of intimacy, both as companions and potentially as competitors. We performed a randomized experiment where participants read of either a robot that could only perform sexual acts, or only engage in non-sexual platonic love relationships. The results of the current study show that females have less positive views of robots, and especially of sex robots, compared to men. Contrary to the expectation rooted in evolutionary psychology, females expected to feel more jealousy if their partner got a sex robot, rather than a platonic love robot. The results further suggests that people project their own feelings about robots onto their partner, erroneously expecting their partner to react as they would to the thought of ones' partner having a robot.


Ultrathin Trilayer Assemblies as Long-Lived Barriers against Water and Ion Penetration in Flexible Bioelectronic Systems.
Biomedical implants that incorporate active electronics and offer the ability to operate in a safe, stable fashion for long periods of time must incorporate defect-free layers as barriers to biofluid penetration. This paper reports an engineered material approach to this challenge that combines ultrathin, physically transferred films of silicon dioxide (t-SiO2) thermally grown on silicon wafers, with layers of hafnium oxide (HfO2) formed by atomic layer deposition and coatings of parylene (Parylene C) created by chemical vapor deposition, as a dual-sided encapsulation structure for flexible bioelectronic systems. Accelerated aging tests on passive/active components in platforms that incorporate active, silicon-based transistors suggest that this trilayer construct can serve as a robust, long-lived, defect-free barrier to phosphate-buffered saline (PBS) solution at a physiological pH of 7.4. Reactive diffusion modeling and systematic immersion experiments highlight fundamental aspects of water diffusion and hydrolysis behaviors, with results that suggest lifetimes of many decades at physiological conditions. A combination of ion-diffusion tests under continuous electrical bias, measurements of elemental concentration profiles, and temperature-dependent simulations reveals that this encapsulation strategy can also block transport of ions that would otherwise degrade the performance of the underlying electronics. These findings suggest broad utility of this trilayer assembly as a reliable encapsulation strategy for the most demanding applications in chronic biomedical implants and high-performance flexible bioelectronic systems.


Drug treatment strategies for epilepsy revisited: starting early or late? One drug or several drugs?
There are two popular strategies for current drug treatment of epilepsy; starting early may be better and polytherapy conveys advantages over monotherapy. This review briefly examines if the historical record is much of a guide to determine the clinical value of these two strategies. Great clinical scientists of the 19th and early 20th century, such as Sir William Gowers, and William Aldren Turner, offered vivid single case studies and showed early results of seizure remission in groups of subjects. The historical record offered, however, no evidence of clear clinical benefits for early treatment and polytherapy. Combination treatment was thought to be useful in only some cases. In agreement, current evidence shows no clear clinical benefit of starting treatment early, except perhaps in severe epilepsy. Polytherapy is clinically useful in a subgroup of subjects, but despite being a standard treatment strategy for over one hundred years, it has been poorly studied. In fact, there is no compelling experimental or clinical evidence for a difference in seizure outcome between monotherapy and polytherapy. This surprising finding should prompt a re-appraisal regarding the need to test both strategies separately for the licensing of new antiepileptic drugs.


Meta-analyses of the effectiveness of intravenous immune globulin for prevention and treatment of neonatal sepsis.
To determine the effectiveness of intravenous immune globulin (IVIG) in the prevention and treatment of neonatal sepsis. All published studies of IVIG for the prevention or treatment of neonatal sepsis were reviewed. Peer-reviewed, prospective, randomized trials with high merit were analyzed by two meta-analyses. The effect of prophylactic IVIG was evaluated by comparison of the numbers of cases of sepsis (bacteremia in the presence of systemic manifestations of sepsis), and of therapeutic IVIG by comparison of the numbers of deaths resulting from early-onset sepsis. Meta-analysis of 4933 evaluable newborns in 12 studies of IVIG prophylaxis showed a statistically significant negative association with the incidence of sepsis in premature low birth weight newborns given IVIG shortly after birth (P = .0193, two-sided). The heterogeneity across these studies precluded estimation of a common odds ratio. Meta-analysis of 110 evaluable cases of neonatal sepsis in three studies of IVIG treatment of neonatal sepsis showed a significant decrease in the mortality rate for neonates with sepsis given IVIG (P = .007, two-sided). The common odds ratio was .173 (95% confidence interval = .031 to .735). Using conservative and objective outcome rating criteria, the addition of IVIG to standard therapies is of minimal but demonstrable benefit in preventing sepsis when administered prophylactically to premature low birth weight newborns, and of unequivocal benefit in preventing death when administered therapeutically for early-onset neonatal sepsis. The likelihood of newborns with sepsis living past the neonatal period was improved nearly sixfold when IVIG was administered in addition to standard therapies.


Transcriptome analysis in Parhyale hawaiensis reveal sex-specific responses to AgNP and AgCl exposure.
Analysis of the transcriptome of organisms exposed to toxicants offers new insights for ecotoxicology, but further research is needed to enhance interpretation of results and effectively incorporate them into useful environmental risk assessments. Factors that must be clarified to improve use of transcriptomics include assessment of the effect of organism sex within the context of toxicant exposure. Amphipods are well recognized as model organisms for toxicity evaluation because of their sensitivity and amenability to laboratory conditions. To investigate whether response to metals in crustaceans differs according to sex we analyzed the amphipod Parhyale hawaiensis after exposure to AgCl and Ag nanoparticles (AgNP) via contaminated food. Gene specific analysis and whole genome transcriptional profile of male and female organisms were performed by both RT-qPCR and RNA-seq. We observed that expression of transcripts of genes glutathione transferase (GST) did not differ among AgCl and AgNP treatments. Significant differences between males and females were observed after exposure to AgCl and AgNP. Males presented twice the number of differentially expressed genes in comparison to females, and more differentially expressed were observed after exposure to AgNP than AgCl treatments in both sexes. The genes that had the greatest change in expression relative to control were those genes related to peptidase and catalytic activity and chitin and carbohydrate metabolic processes. Our study is the first to demonstrate sex specific differences in the transcriptomes of amphipods upon exposure to toxicants and emphasizes the importance of considering gender in ecotoxicology.


A comparative investigation of mussel-mimetic sealants for fetal membrane repair.
Towards the prevention of iatrogenic preterm premature rupture of the fetal membrane, two mussel-mimetic tissue adhesives (cT and cPEG) have been compared and qualified as possible sealants for membrane repair. Monotonic and cyclic inflation tests of repaired fetal membranes were carried out in order to investigate the performance of the glues under quasi-static, fast, and repeated loading. Finite element simulations of repaired and inflated synthetic membranes allowed to compare cT and cPEG under large deformations. Both adhesives seal the membrane well, resisting pressures higher than the intra-uterine baseline. Only under repeated mechanical load, as well as under fast and acute deformation of the membrane, the sealing performance has deteriorated. Even though cT loses adhesion to the deformed membrane, it is able to withstand high deformations and pressures without rupturing, while cPEG breaks.


The potential effects of chlorogenic acid, the main phenolic components in coffee, on health: a comprehensive review of the literature.
Chlorogenic acid (CGA), an important biologically active dietary polyphenol, is produced by certain plant species and is a major component of coffee. Reduction in the risk of a variety of diseases following CGA consumption has been mentioned in recent basic and clinical research studies. This systematic review discusses in vivo animal and human studies of the physiological and biochemical effects of chlorogenic acids (CGAs) on biomarkers of chronic disease. We searched PubMed, Embase, Amed and Scopus using the following search terms: ("chlorogenic acid" OR "green coffee bean extract") AND (human OR animal) (last performed on April 1st, 2015) for relevant literature on the in vivo effects of CGAs in animal and human models, including clinical trials on cardiovascular, metabolic, cancerogenic, neurological and other functions. After exclusion of editorials and letters, uncontrolled observations, duplicate and not relevant publications the remaining 94 studies have been reviewed. The biological properties of CGA in addition to its antioxidant and anti-inflammatory effects have recently been reported. It is postulated that CGA is able to exert pivotal roles on glucose and lipid metabolism regulation and on the related disorders, e.g. diabetes, cardiovascular disease (CVD), obesity, cancer, and hepatic steatosis. The wide range of potential health benefits of CGA, including its anti-diabetic, anti-carcinogenic, anti-inflammatory and anti-obesity impacts, may provide a non-pharmacological and non-invasive approach for treatment or prevention of some chronic diseases. In this study, the effects of CGAs on different aspects of health by reviewing the related literatures have been discussed.


Coexpression of survivin and PCNA in pituitary tumors and normal pituitary.
The survivin is the protein involved in regulation of basic and cycle-specific functions of cells both in normal and cancer tissue. Recent studies present survivin as a factor having the leading role in the regulation of apoptosis and mitosis as well as a target of anticancer therapy. The employing of survivin in this therapy is based on its high expression level in most human cancers, as well as its association with the disease's progression. The aim of our study was to evaluate the expression and localization of survivin's gene product on the protein level in different types of pituitary tumors and normal pituitary. The coexpression of survivin and proliferating cell nuclear antigen - PCNA in pituitary was also examined. The study was conducted on the postoperative pituitary tumors tissue taken during standard neurosurgical removal of tumor from 43 patients. The group of patients consists of 23 women and 20 men, aged from 27 to 71 years. As a control of the study three normal pituitary tissues obtained at the autopsy were used. Evaluation of survivin and PCNA expression was performed using immunohistochemical staining. The study demonstrated the presence of survivin in all analyzed by us pituitary tumors. Survivin was present also in normal pituitary tissue. The protein was localized mainly in cell's nuclei, however the less intense immunostaining was observed also in the cytoplasm of pituitary tumors cells. Furthermore survivin was found in normal pituitary, but the positive immunostaining was limited to a single cells. The analysis of pituitary tumor cells proliferation index based on PCNA reactivity showed that survivin is coexpressed with PCNA, especially in invasive tumors. The study documented the presence of survivin in different types of pituitary tumors as well as in normal pituitary. Additionally the coexpression of survivin and PCNA in tumor cells was shown. The expression of survivin in both normal and cancer pituitary cells suggests that it may play an important role in regulation of the gland's proliferation.


Flucytosine resistance in Cryptococcus gattii is indirectly mediated by the FCY2-FCY1-FUR1 pathway.
Cryptococcosis is an opportunistic fungal infection caused by members of the two sibling species complexes: Cryptococcus neoformans and Cryptococcus gattii. Flucytosine (5FC) is one of the most widely used antifungals against Cryptococcus spp., yet very few studies have looked at the molecular mechanisms responsible for 5FC resistance in this pathogen. In this study, we examined 11 C. gattii clinical isolates of the major molecular type VGIII based on differential 5FC susceptibility and asked whether there were genomic changes in the key genes involved in flucytosine metabolism. Susceptibility assays and sequencing analysis revealed an association between a point mutation in the cytosine deaminase gene (FCY1) and 5FC resistance in two of the studied 5FC resistant C. gattii VGIII clinical isolates, B9322 and JS5. This mutation results in the replacement of arginine for histidine at position 29 and occurs within a variable stretch of amino acids. Heterologous expression of FCY1 and spot sensitivity assays, however, demonstrated that this point mutation did not have any effect on FCY1 activities and was not responsible for 5FC resistance. Comparative sequence analysis further showed that no changes in the amino acid sequence and no genomic alterations were observed within 1 kb of the upstream and downstream sequences of either cytosine permeases (FCY2-4) or uracil phosphoribosyltransferase (FUR1) genes in 5FC resistant and 5FC susceptible C. gattii VGIII isolates. The herein obtained results suggest that the observed 5FC resistance in the isolates B9322 and JS5 is due to changes in unknown protein(s) or pathway(s) that regulate flucytosine metabolism.


Cytoplasmic tails of bunyavirus Gn glycoproteins-Could they act as matrix protein surrogates?
Viruses of the family Bunyaviridae are negative-sense RNA viruses (NRVs). Unlike other NRVs bunyaviruses do not possess a matrix protein, which typically facilitates virus release from host cells and acts as an anchor between the viral membrane and its genetic core. Therefore the functions of matrix protein in bunyaviruses need to be executed by other viral proteins. In fact, the cytoplasmic tail of glycoprotein Gn (Gn-CT) of various bunyaviruses interacts with the genetic core (nucleocapsid protein and/or genomic RNA). In addition the Gn-CT of phleboviruses (a genus in the family Bunyaviridae) has been demonstrated to be essential for budding. This review brings together what is known on the role of various bunyavirus Gn-CTs in budding and assembly, and hypothesizes on their yet unrevealed functions in viral life cycle by comparing to the matrix proteins of NRVs.


The Succinated Proteome of FH-Mutant Tumours.
Inherited mutations in the Krebs cycle enzyme fumarate hydratase (FH) predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC). Loss of FH activity in HLRCC tumours causes accumulation of the Krebs cycle intermediate fumarate to high levels, which may act as an oncometabolite through various, but not necessarily mutually exclusive, mechanisms. One such mechanism, succination, is an irreversible non-enzymatic modification of cysteine residues by fumarate, to form S-(2-succino)cysteine (2SC). Previous studies have demonstrated that succination of proteins including glyceraldehyde 3-phosphate dehydrogenase (GAPDH), kelch-like ECH-associated protein 1 (KEAP1) and mitochondrial aconitase (ACO2) can have profound effects on cellular metabolism. Furthermore, immunostaining for 2SC is a sensitive and specific biomarker for HLRCC tumours. Here, we performed a proteomic screen on an FH-mutant tumour and two HLRCC-derived cancer cell lines and identified 60 proteins where one or more cysteine residues were succinated; 10 of which were succinated at cysteine residues either predicted, or experimentally proven, to be functionally significant. Bioinformatic enrichment analyses identified most succinated targets to be involved in redox signaling. To our knowledge, this is the first proteomic-based succination screen performed in human tumours and cancer-derived cells and has identified novel 2SC targets that may be relevant to the pathogenesis of HLRCC.


NF45 and NF90 Regulate Mitotic Gene Expression by Competing with Staufen-Mediated mRNA Decay.
In human cells, the expression of ∼1,000 genes is modulated throughout the cell cycle. Although some of these genes are controlled by specific transcriptional programs, very little is known about their post-transcriptional regulation. Here, we analyze the expression signature associated with all 687 RNA-binding proteins (RBPs) and identify 39 that significantly correlate with cell cycle mRNAs. We find that NF45 and NF90 play essential roles in mitosis, and transcriptome analysis reveals that they are necessary for the expression of a subset of mitotic mRNAs. Using proteomics, we identify protein clusters associated with the NF45-NF90 complex, including components of Staufen-mediated mRNA decay (SMD). We show that depletion of SMD components increases the binding of mitotic mRNAs to the NF45-NF90 complex and rescues cells from mitotic defects. Together, our results indicate that the NF45-NF90 complex plays essential roles in mitosis by competing with the SMD machinery for a common set of mRNAs.


Hip MRI: how useful is intraarticular contrast material for evaluating surgically proven lesions of the labrum and articular cartilage?
The objective of our study was to prospectively compare the diagnostic performance of MR arthrography and conventional MRI with surgical correlation in the same patient for detecting labrum and articular cartilage defects. Twenty-eight patients (mean age, 31.8 years) underwent MR arthrography, conventional MRI, and subsequent hip surgery, which served as the reference standard. Labrum and cartilage defects were evaluated at MRI by two independent readers. A McNemar test and kappa statistics were used for statistical analysis. At surgery, 31 labral tears were identified. MR arthrography had an advantage over conventional MRI for detecting labral tears at the anterosuperior quadrant (sensitivity of MR arthrography, 81% and 69% for readers 1 and 2, respectively; sensitivity of conventional MRI, 50% for both readers); this difference in performance between MR arthrography and conventional MRI was statistically significant for reader 1 (p = 0.02) but not for reader 2 (p = 0.2). Interobserver agreement for labral tears was higher for MR arthrography (κ = 0.81) than for conventional MRI (κ = 0.63). Surgery showed 31 acetabular cartilage defects and nine femoral cartilage defects. MR arthrography had an advantage over conventional MRI for detecting acetabular cartilage defects (sensitivity of MR arthrography, 71% and 92% for readers 1 and 2, respectively; sensitivity of conventional MRI, 58% and 83%), whereas there was no advantage to using MR arthrography for detecting femoral cartilage defects with statistically significant difference for the acetabular cartilage or femoral cartilage. Interobserver agreement was slightly higher for MR arthrography (κ = 0.50) than for conventional MRI (κ = 0.40) for assessing the acetabular cartilage and was almost identical for the femoral cartilage (κ = 0.62 and 0.63, respectively). MR arthrography was superior to conventional MRI for detecting labral tears and acetabular cartilage defects and showed a higher interobserver agreement. For femoral cartilage lesions, both modalities yielded comparable results.


Vascular risk factors and depression in later life: a systematic review and meta-analysis.
Reports of the association between cardiovascular risk factors and depression in later life are inconsistent; to establish the nature of their association seems important for prevention and treatment of late-life depression. We searched MEDLINE, EMBASE, and PsycINFO for relevant cohort or case control studies over the last 22 years; 1097 were retrieved; 26 met inclusion criteria. Separate meta-analyses were performed for Risk Factor Composite Scores (RFCS) combining different subsets of risk factors, Framingham Stroke Risk Score, and single factors. We found a positive association (odds ratio [OR]: 1.49; 95% confidence interval [CI]: 1.27-1.75) between RFCS and late-life depression. There was no association between Framingham Stroke Risk Score (OR: 1.25; 95% CI: .99-1.57), hypertension (OR: 1.14; 95% CI: .94-1.40), or dyslipidemia (OR: 1.08; 95% CI: .91-1.28) and late-life depression. The association with smoking was weak (OR: 1.35; 95% CI: 1.00-1.81), whereas positive associations were found with diabetes (OR: 1.51; 95% CI: 1.30-1.76), cardiovascular disease (OR: 1.76; 95% CI: 1.52-2.04), and stroke (OR: 2.11; 95% CI: 1.61-2.77). Moderate to high heterogeneity was found in the results for RFCS, smoking, hypertension, dyslipidemia, and stroke, whereas publication bias was detected for RFCS and diabetes. We therefore found convincing evidence of a strong relationship between key diseases and depression (cardiovascular disease, diabetes, and stroke) and between composite vascular risk and depression but not between some vascular risk factors (hypertension, smoking, dyslipidemia) and depression. More evidence is needed to be accumulated from large longitudinal epidemiological studies, particularly if complemented by neuroimaging.


Mycobacterium tuberculosis infection of host cells in space and time.
Tuberculosis (TB) caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb) remains one of the deadliest infectious diseases with over a billion deaths in the past 200 years (Paulson 2013). TB causes more deaths worldwide than any other single infectious agent, with 10.4 million new cases and close to 1.7 million deaths in 2017. The obstacles that make TB hard to treat and eradicate are intrinsically linked to the intracellular lifestyle of Mtb. Mtb needs to replicate within human cells to disseminate to other individuals and cause disease. However, we still do not completely understand how Mtb manages to survive within eukaryotic cells and why some cells are able to eradicate this lethal pathogen. Here, we summarise the current knowledge of the complex host cell-pathogen interactions in TB and review the cellular mechanisms operating at the interface between Mtb and the human host cell, highlighting the technical and methodological challenges to investigating the cell biology of human host cell-Mtb interactions.


Image dehazing using polarization effects of objects and airlight.
The analysis of polarized filtered images has been proven useful in image dehazing. However, the current polarization-based dehazing algorithms are based on the assumption that the polarization is only associated with the airlight. This assumption does not hold up well in practice since both object radiance and airlight contribute to the polarization. In this study, a new polarization hazy imaging model is presented, which considers the joint polarization effects of the airlight and the object radiance in the imaging process. In addition, an effective method to synthesize the optimal polarized-difference (PD) image is introduced. Then, a decorrelation-based scheme is proposed to estimate the degree of polarization for the object from the polarized image input. After that, the haze-free image can be recovered based on the new polarization hazy imaging model. The qualitative and quantitative experimental results verify the effectiveness of this new dehazing scheme. As a by-product, this scheme also provides additional polarization properties of the objects in the image, which can be used in extended applications, such as scene segmentation and object recognition.


In vitro investigation of the factors affecting pulse oximetry.
The effect of a number of physiological parameters on pulse oximetry accuracy has been investigated in an in vitro model. We have found that above 50% saturation, pulse oximeters will not be affected by variations in haematocrit, blood flow rate, tissue blood content and pulse amplitude. At low saturations, however, it is known that the accuracy of pulse oximeters decreases and our in vitro results suggest how this may be corrected.


CD40 gene polymorphisms confer risk of Behcet's disease but not of Vogt-Koyanagi-Harada syndrome in a Han Chinese population.
Recent genetic surveys including a genome-wide association study have identified CD40 as a susceptibility gene for several autoimmune diseases. This study was designed to investigate the association of CD40 gene polymorphisms with Behçet's disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome in a Han Chinese population. Two single nucleotide polymorphisms (SNPs), rs4810485 and rs1883832, were genotyped using polymerase chain reaction-restriction fragment length polymorphism in 373 BD patients, 519 VKH patients and 402 controls. A binary logistic regression analysis was applied to assess the influence of gender on the association of CD40 polymorphisms with BD. Our results showed significantly increased frequencies of the homozygous rs4810485 TT and rs1883832 TT in BD patients as compared with the controls [Bonferroni-corrected P-value for gender adjustment (Pac) = 0.006, odds ratio (OR) = 1.98, 95% confidence interval (CI) 1.38, 2.83; = 0.012, OR = 1.73, 95% CI 1.22, 2.46, respectively]. A markedly decreased frequency of the heterozygous rs4810485 GT was observed in BD patients as compared with the controls ( = 0.042, OR = 0.68, 95% CI 0.51, 0.90). The genotype and allele frequencies of rs4810485 and rs1883832 were not different between VKH patients and controls. Stratification analysis did not find any association between the tested SNPs and extra-ocular manifestations of both diseases. The results suggest that TT genotypes of rs4810485 and rs1883832 may be predisposing genotypes for BD, and that the rs4810485 GT genotype may be a protective genotype for BD. The two tested CD40 gene polymorphisms are not associated with VKH syndrome in the investigated Han Chinese population.


Induced sputum and bronchial mucosal expression of interleukin-13 is not increased in chronic obstructive pulmonary disease.
The Th2 cytokine interleukin-13 (IL-13) has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). We sought to examine IL-13 expression in COPD subjects in induced sputum and bronchus specimens. We hypothesized that inflammatory cells expressing IL-13 localize to the airway smooth muscle bundle and bronchial glands. Interleukin-13 was measured in sputum samples from subjects with COPD (n = 34) across a range of severity (Global initiative for chronic Obstructive Lung Disease 2-4) and controls (n = 14) using ELISA. IL-13+ cells and inflammatory cells were enumerated within surgically resected proximal airway using immunohistochemical techniques from subjects with COPD (n = 10), smoking (n = 10) and nonsmoking controls (n = 8). Sputum IL-13 was measurable in only 6/34 subjects with COPD and was not found in the smoking or nonsmoking control subjects. In subjects with COPD and controls there was a paucity of IL-13+ cells. The distribution of inflammatory cells within different airway compartments was similar in COPD and controls except for an increase in CD3(+) lymphocytes within bronchial glands in COPD (P = 0.04). Our findings do not support a role for IL-13 in COPD. However, the tissue localization of inflammatory cells to airway compartments, particularly the increase of T cells in glands in COPD may be important in disease.


Clozapine withdrawal-emergent dystonias and dyskinesias: a case series.
Severe psychotic decompensation during clozapine withdrawal has been reported previously. Less attention has been paid to movement disorders following abrupt clozapine withdrawal. This report describes 4 subjects who experienced severe dystonias and dyskinesias upon abrupt clozapine withdrawal. Current and past medical records of 4 subjects with DSM-IV schizophrenia or schizo-affective disorder were reviewed. All subjects had a history of neuroleptic-induced extrapyramidal symptoms, 1 had a history of severe dystonias, and 1 had neuroleptic malignant syndrome. All had mild orolingual tardive dyskinesia prior to clozapine treatment. All subjects had received clozapine for several months, and 3 of the 4 subjects stopped clozapine abruptly. Two subjects experienced cholinergic rebound symptoms within hours, which resolved quickly. These subjects had severe limb-axial and neck dystonias and dyskinesias 5 to 14 days after clozapine withdrawal. Two subjects were unable to ambulate, and 1 had a lurching gait. Two gagged while eating or drinking. Two subjects were returned to clozapine, 1 was started on low-dose risperidone treatment, and 1 was started on olanzapine treatment. All experienced significant improvements in their mental state and movement disorders. Severe movement disorders, which may be worse than the movements prior to clozapine treatment, and cholinergic rebound symptoms may occur upon abrupt clozapine withdrawal and must be recognized in addition to the severe psychotic decompensation noted in some patients. Patients, families, and caregivers must be alerted to this possibility. Where possible, a slow clozapine taper, the use of anticholinergic agents, and symptomatic treatment may help minimize these withdrawal symptoms, and reintroduction of clozapine or treatment with the newer atypical agents can help in the clinical management of these symptoms.


The Drosophila melanogaster homologue of an insect calcitonin-like diuretic peptide stimulates V-ATPase activity in fruit fly Malpighian tubules.
The Drosophila melanogaster homologue of an insect calcitonin-like diuretic hormone was identified in a BLAST search of the Drosophila genome database. The predicted 31-residue amidated peptide (D. melanogaster DH31; Drome-DH31) was synthesised and tested for activity on fruit fly Malpighian tubules. It increases tubule secretion by approximately 35 % of the response obtained with a myokinin from the housefly Musca domestica (muscakinin; Musdo-K) and has an EC50 of 4.3 nmol x l(-1). The diuretic activities of Drome-DH31 and Musdo-K were additive when tested at threshold and supra-maximal concentrations, which suggests that they target different transport processes. In support of this, Drome-DH31 increased the rate of secretion by tubules held in bathing fluid with a reduced Cl- concentration, whereas Musdo-K did so only in the presence of Drome-DH31. Stimulation with Drome-DH31 increased the lumen-positive transepithelial potential in the main secretory segment of the tubule. This was attributed to activation of an apical electrogenic proton-translocating V-ATPase in principal cells, since it was associated with hyperpolarisation of the apical membrane potential and acidification of secreted urine by 0.25 pH units. Exogenous 8-bromo-cyclic AMP and cyclic GMP increased tubule secretion to the same extent as Drome-DH31 and, when tested together with the diuretic peptide, their activities were not additive. Stimulation with Drome-DH31 resulted in a dose-dependent increase in cyclic AMP production by tubules incubated in saline containing 0.5 mmol x l(-1) 3-isobutyl-1-methylxanthine, whereas cyclic GMP production was unchanged. Taken together, the data are consistent with Drome-DH31 activating an apical membrane V-ATPase via cyclic AMP. Since the K+ concentration of the secreted urine was unchanged, it is likely that Drome-DH31 has an equal effect on K+ and Na+ entry across the basolateral membrane.


The Causative Classification of Stroke system: an international reliability and optimization study.
Valid and reliable ischemic stroke subtype determination is crucial for well-powered multicenter studies. The Causative Classification of Stroke System (CCS, available at http://ccs.mgh.harvard.edu) is a computerized, evidence-based algorithm that provides both causative and phenotypic stroke subtypes in a rule-based manner. We determined whether CCS demonstrates high interrater reliability in order to be useful for international multicenter studies. Twenty members of the International Stroke Genetics Consortium from 13 centers in 8 countries, who were not involved in the design and development of the CCS, independently assessed the same 50 consecutive patients with acute ischemic stroke through reviews of abstracted case summaries. Agreement among ratings was measured by kappa statistic. The κ value for causative classification was 0.80 (95% confidence interval [CI] 0.78-0.81) for the 5-subtype, 0.79 (95% CI 0.77-0.80) for the 8-subtype, and 0.70 (95% CI 0.69-0.71) for the 16-subtype CCS. Correction of a software-related factor that generated ambiguity improved agreement: κ = 0.81 (95% CI 0.79-0.82) for the 5-subtype, 0.79 (95% CI 0.77-0.80) for the 8-subtype, and 0.79 (95% CI 0.78-0.80) for the 16-subtype CCS. The κ value for phenotypic classification was 0.79 (95% CI 0.77-0.82) for supra-aortic large artery atherosclerosis, 0.95 (95% CI 0.93-0.98) for cardioembolism, 0.88 (95% CI 0.85-0.91) for small artery occlusion, and 0.79 (0.76-0.82) for other uncommon causes. CCS allows classification of stroke subtypes by multiple investigators with high reliability, supporting its potential for improving stroke classification in multicenter studies and ensuring accurate means of communication among different researchers, institutions, and eras.


Prediction of disease and phenotype associations from genome-wide association studies.
Genome wide association studies (GWAS) have proven useful as a method for identifying genetic variations associated with diseases. In this study, we analyzed GWAS data for 61 diseases and phenotypes to elucidate common associations based on single nucleotide polymorphisms (SNP). The study was an expansion on a previous study on identifying disease associations via data from a single GWAS on seven diseases. Adjustments to the originally reported study included expansion of the SNP dataset using Linkage Disequilibrium (LD) and refinement of the four levels of analysis to encompass SNP, SNP block, gene, and pathway level comparisons. A pair-wise comparison between diseases and phenotypes was performed at each level and the Jaccard similarity index was used to measure the degree of association between two diseases/phenotypes. Disease relatedness networks (DRNs) were used to visualize our results. We saw predominant relatedness between Multiple Sclerosis, type 1 diabetes, and rheumatoid arthritis for the first three levels of analysis. Expected relatedness was also seen between lipid- and blood-related traits. The predominant associations between Multiple Sclerosis, type 1 diabetes, and rheumatoid arthritis can be validated by clinical studies. The diseases have been proposed to share a systemic inflammation phenotype that can result in progression of additional diseases in patients with one of these three diseases. We also noticed unexpected relationships between metabolic and neurological diseases at the pathway comparison level. The less significant relationships found between diseases require a more detailed literature review to determine validity of the predictions. The results from this study serve as a first step towards a better understanding of seemingly unrelated diseases and phenotypes with similar symptoms or modes of treatment.


Management of pancreatic neuroendocrine tumors in patients with MEN 1.
Pancreatic neuroendocrine tumors (PNETs) are frequent and can be non-functional (NF) in patients with multiple endocrine neoplasia type 1 (MEN1). Their identification is of clinical importance because malignant PNETs are reported to be the most common cause of death in patients with MEN1. Once the diagnosis of MEN1 is established in an individual based on clinical manifestations and/or genetic testing results, an active surveillance program is instituted for early detection and treatment of MEN1-associated disease. Ultrasonography, endoscopic ultrasonography (EUS), CT, MRI, selective arterial angiography and somatostatin receptor scintigraphy are all used for localization of tumors. Managing PNETs can be challenging and includes diagnosis, surveillance, adequate staging, and interdisciplinary, multimodal treatments to optimize patient outcome. Treatment includes surgical resection for loco-regional disease, as well as liver directed and targeted chemotherapies for advanced progressive disease. To date, the recommendation for surgical resection in NF-PNETs is based on tumor size, as a higher rate of metastases was found in patients with larger tumors. This review summarizes key concepts in managing PNETs in patients with MEN1.


Undergraduate Students' Critical Online Reasoning-Process Mining Analysis.
To successfully learn using open Internet resources, students must be able to critically search, evaluate and select online information, and verify sources. Defined as critical online reasoning (COR), this construct is operationalized on two levels in our study: (1) the student level using the newly developed Critical Online Reasoning Assessment (CORA), and (2) the online information processing level using event log data, including gaze durations and fixations. The written responses of 32 students for one CORA task were scored by three independent raters. The resulting score was operationalized as "task performance," whereas the gaze fixations and durations were defined as indicators of "process performance." Following a person-oriented approach, we conducted a process mining (PM) analysis, as well as a latent class analysis (LCA) to test whether-following the dual-process theory-the undergraduates could be distinguished into two groups based on both their process and task performance. Using PM, the process performance of all 32 students was visualized and compared, indicating two distinct response process patterns. One group of students (11), defined as "strategic information processers," processed online information more comprehensively, as well as more efficiently, which was also reflected in their higher task scores. In contrast, the distributions of the process performance variables for the other group (21), defined as "avoidance information processers," indicated a poorer process performance, which was also reflected in their lower task scores. In the LCA, where two student groups were empirically distinguished by combining the process performance indicators and the task score as a joint discriminant criterion, we confirmed these two COR profiles, which were reflected in high vs. low process and task performances. The estimated parameters indicated that high-performing students were significantly more efficient at conducting strategic information processing, as reflected in their higher process performance. These findings are so far based on quantitative analyses using event log data. To enable a more differentiated analysis of students' visual attention dynamics, more in-depth qualitative research of the identified student profiles in terms of COR will be required.


Impact of a 2-year multimodal intervention for disruptive 6-year-olds on substance use in adolescence: randomised controlled trial.
Adolescent substance use is associated with both earlier childhood behavioural problems and serious lifetime addiction problems later in life. To examine whether, and through which mechanisms, targeting risk factors in early childhood prevents substance use across adolescence. Disruptive kindergarten boys (n = 172) living in Montreal were randomly allocated to a preventive intervention and a control condition. The intervention was delivered over 2 years (7-9 years of age) with two main components: (a) social and problem-solving skills training for the boys; and (b) training for parents on effective child-rearing skills. Adolescent substance use, up to 8 years post-intervention, was reduced in those who received the intervention (d = 0.48-0.70). Of most interest, the intervention effects were explained partly by reductions in impulsivity, antisocial behaviour and affiliation with less deviant peers during pre-adolescence (11-13 years). Adolescent substance use may be indirectly prevented by selectively targeting childhood risk factors that disrupt the developmental cascade of adolescent risk factors for substance use.


Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from a multidisciplinary expert panel.
Noncognitive neuropsychiatric symptoms (NPS) of dementia (aggression, agitation, depression, anxiety, delusions, hallucinations, apathy, disinhibition) affect individuals with dementia nearly universally across dementia stages and etiologies. NPS are associated with poor outcomes for individuals with dementia and caregivers, including excess morbidity and mortality, greater healthcare use, and earlier nursing home placement, as well as caregiver stress, depression, and difficulty with employment. Although the Food and Drug Administration has not approved pharmacotherapy for NPS, psychotropic medications are frequently used to manage these symptoms, but in the few cases of proven pharmacological efficacy, significant risk of adverse effects may offset benefits. There is evidence of efficacy and limited potential for adverse effects of nonpharmacological treatments, typically considered first line, but their uptake as preferred treatments remains inadequate in real-world clinical settings. Thus, the field currently finds itself in a predicament in terms of management of these difficult symptoms. It was in this context that the University of Michigan Program for Positive Aging, working in collaboration with the Johns Hopkins Alzheimer's Disease Research Center and Center for Innovative Care in Aging sponsored and convened a multidisciplinary expert panel in Detroit, Michigan, in fall 2011 with three objectives: to define critical elements of care for NPS in dementia; to construct an approach describing the sequential and iterative steps of managing NPS in real-world clinical settings that can be used as a basis for integrating nonpharmacological and pharmacological approaches; and to discuss how the approach generated could be implemented in research and clinical care.


Definitions of histocompatibility typing terms: Harmonization of Histocompatibility Typing Terms Working Group.
Histocompatibility testing for stem cell and solid organ transplantation has become increasingly complex as newly discovered human leukocyte antigen (HLA) alleles are described. HLA typing assignments reported by laboratories are used by physicians and donor registries for matching donors and recipients. To communicate effectively, a common language for histocompatibility terms should be established. In early 2010, representatives from clinical, registry, and histocompatibility organizations joined together as the Harmonization of Histocompatibility Typing Terms Working Group to define a consensual language for laboratories, physicians and registries to communicate histocompatibility typing information. The Working Group defined terms for HLA typing resolution, HLA matching and a format for reporting HLA assignments. In addition, definitions of verification typing and extended typing were addressed. The original draft of the Definitions of Histocompatibility Typing Terms was disseminated to colleagues from each organization to gain feedback and create a collaborative document. Commentary gathered during this 90-day review period were discussed and implemented for preparation of this report. Histocompatibility testing continues to evolve thus, the definitions agreed upon today, likely will require refinement and perhaps additional terminology in the future.


Anti-inflammatory actions of interleukin-13: suppression of tumor necrosis factor-alpha and antigen-induced leukocyte accumulation in the guinea pig lung.
The Th2 cytokine interleukin (IL)-13 is believed to play an important role in the development of allergy, although it has also been ascribed anti-inflammatory roles in several experimental models. In this study, we have examined the effects of human recombinant IL-13 on eosinophilic lung inflammation in the guinea pig. IL-13 (1 to 100 ng, given by intratracheal instillation) did not elicit airway eosinophil recruitment. A pronounced accumulation of eosinophils, as well as monocyte/macrophages, was elicited by intratracheal instillation of guinea pig tumor necrosis factor alpha (gpTNF-alpha). Intratracheal administration of IL-13 (1 to 100 ng) given immediately prior to exposure to gpTNF-alpha resulted in a dose-related suppression of eosinophil and monocyte/macrophage accumulation in the airways, as assessed by bronchoalveolar lavage (BAL) and eosinophil peroxidase activity in whole-lung homogenates. IL-13 treatment also reduced BAL fluid (BALF) leukocyte accumulation induced by subsequent aerosol antigen challenge of sensitized guinea pigs. Antigen challenge also resulted in elevated levels of immunoreactive eotaxin and eosinophil-stimulating activity in BALF, although only the latter was reduced significantly by IL-13 instillation prior to challenge. In contrast to the suppressive effects of IL-13, instillation of human recombinant IL-4 (100 ng) alone elicited an increase in BALF monocyte/macrophage numbers, and IL-4 was unable to inhibit gpTNF-alpha-induced leukocyte accumulation. Hence, IL-13 (but not human IL-4) exhibits an anti-inflammatory action in the airways of gpTNF-alpha- or antigen-challenged guinea pigs, by mechanisms that may involve the decreased generation of eosinophil-stimulating activity in the airways.


A unique PPARgamma ligand with potent insulin-sensitizing yet weak adipogenic activity.
FMOC-L-Leucine (F-L-Leu) is a chemically distinct PPARgamma ligand. Two molecules of F-L-Leu bind to the ligand binding domain of a single PPARgamma molecule, making its mode of receptor interaction distinct from that of other nuclear receptor ligands. F-L-Leu induces a particular allosteric configuration of PPARgamma, resulting in differential cofactor recruitment and translating in distinct pharmacological properties. F-L-Leu activates PPARgamma with a lower potency, but a similar maximal efficacy, than rosiglitazone. The particular PPARgamma configuration induced by F-L-Leu leads to a modified pattern of target gene activation. F-L-Leu improves insulin sensitivity in normal, diet-induced glucose-intolerant, and in diabetic db/db mice, yet it has a lower adipogenic activity. These biological effects suggest that F-L-Leu is a selective PPARgamma modulator that activates some (insulin sensitization), but not all (adipogenesis), PPARgamma-signaling pathways.


Risk behaviour and noise exposure among adolescents.
Adolescents in Western society often expose themselves to high levels of sound in gyms, rock concerts, discotheques etc. As these behaviours are as threatening to young people's health as more traditional risk behaviours are, our aim in the present study was to analyze the relationship between self-exposure to noise, risk behaviours and risk judgements among 310 Swedish adolescents aged 15-20 (167 men; 143 women). Adolescents' behaviour in different traditional risk situations correlated with behaviour in noisy environments, while judgements about traditional risks correlated with judgements regarding noise exposure. It is an interesting finding that although young women judge risk situations as generally more dangerous than young men do, they nevertheless behave in the same way. We suggest that this difference is a social and cultural phenomenon which underscores the importance of adopting a gender perspective in the analysis of risk factors. Adolescents reporting permanent tinnitus judged loud music as more risky than adolescents with no symptoms and they did not listen to loud music as often as those with occasional tinnitus. Research on hearing prevention for young people needs to acknowledge and make use of theories on risk behaviour, especially due to the existence of a relationship between adolescents' risk-taking in noisy environments and other types of risk-taking. Similarly, theories on risk behaviour should acknowledge noise as a risk factor.


"Vision for Action" in Young Children Aligning Multi-Featured Objects: Development and Comparison with Nonhuman Primates.
Effective vision for action and effective management of concurrent spatial relations underlie skillful manipulation of objects, including hand tools, in humans. Children's performance in object insertion tasks (fitting tasks) provides one index of the striking changes in the development of vision for action in early life. Fitting tasks also tap children's ability to work with more than one feature of an object concurrently. We examine young children's performance on fitting tasks in two and three dimensions and compare their performance with the previously reported performance of adult individuals of two species of nonhuman primates on similar tasks. Two, three, and four year-old children routinely aligned a bar-shaped stick and a cross-shaped stick but had difficulty aligning a tomahawk-shaped stick to a matching cut-out. Two year-olds were especially challenged by the tomahawk. Three and four year-olds occasionally held the stick several inches above the surface, comparing the stick to the surface visually, while trying to align it. The findings suggest asynchronous development in the ability to use vision to achieve alignment and to work with two and three spatial features concurrently. Using vision to align objects precisely to other objects and managing more than one spatial relation between an object and a surface are already more elaborated in two year-old humans than in other primates. The human advantage in using hand tools derives in part from this fundamental difference in the relation between vision and action between humans and other primates.


Shiga toxin-producing Escherichia coli survives storage in wheat flour for two years.
Wheat flour has recently been recognised as an exposure vehicle for the foodborne pathogen Shiga toxin-producing Escherichia coli (STEC). Wheat flour milled on two sequential production days in October 2016, and implicated in a Canada wide outbreak of STEC O121:H19, was analysed for the presence of STEC in November 2018. Stored in sealed containers at ambient temperature, the water activity of individual flour samples was below 0.5 at 6 months post-milling and remained static or decreased slightly in individual samples during 18 months of additional storage. STEC O121 was isolated, with the same genotype (stx2a, eae, hlyA) and core genome multilocus sequence type as previous flour and clinical isolates associated with the outbreak. The result of this analysis demonstrates the potential for STEC to persist in wheat flour at levels associated with outbreak infections for periods of up to two years. This has implications for the potential for STEC to survive in other foods with low water activity.


[Governance and regulation in health: challenges for health management in Greater Metropolitan São Paulo, Brazil].
This paper discusses the relationship between the public and private sectors in the Unified National Health System (SUS), based on research whose objective was to identify governance strategies and mechanisms for public/private relations in the health sector, considering the search for equity in Greater Metropolitan Sao Paulo, Brazil. Governance was used as an analytical category, with health system regulation as the issue. Municipal and State health secretaries, members of health councils, and SUS staff were interviewed, and the empirical material was classified as: (a) regulatory mechanisms and instruments; (b) power loci; and (c) actors' positions concerning the SUS and its relationship to the private sector. Mechanisms and instruments have been created and used in the municipalities for regulation of their own services. Regulatory measures for the complementary and supplementary healthcare sector are practically nonexistent. There are numerous institutional power loci, seen more as places for submitting demands than as forums for negotiation. Despite some progress, governance appears to be more of a formal issue. Discussion is needed on the relationship between the public and private sectors and its regulation by municipalities in order to improve the health system.


Election turnout statistics in many countries: similarities, differences, and a diffusive field model for decision-making.
We study in details the turnout rate statistics for 77 elections in 11 different countries. We show that the empirical results established in a previous paper for French elections appear to hold much more generally. We find in particular that the spatial correlation of turnout rates decay logarithmically with distance in all cases. This result is quantitatively reproduced by a decision model that assumes that each voter makes his mind as a result of three influence terms: one totally idiosyncratic component, one city-specific term with short-ranged fluctuations in space, and one long-ranged correlated field which propagates diffusively in space. A detailed analysis reveals several interesting features: for example, different countries have different degrees of local heterogeneities and seem to be characterized by a different propensity for individuals to conform to the cultural norm. We furthermore find clear signs of herding (i.e., strongly correlated decisions at the individual level) in some countries, but not in others.


Mice with type 2 and 3 Gaucher disease point mutations generated by a single insertion mutagenesis procedure.
Gaucher disease is caused by mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GC). Three clinical types of Gaucher disease have been defined according to the presence (type 2 and 3) or absence (type 1) of central nervous system disease and severity of clinical manifestations. The clinical course of the disease correlates with the mutation carried by the GC gene. To produce mice with point mutations that correspond to the clinical types of Gaucher disease, we have devised a highly efficient one-step mutagenesis method-the single insertion mutagenesis procedure (SIMP)-to introduce human disease mutations into the mouse GC gene. By using SIMP, mice were generated carrying either the very severe RecNciI mutation that can cause type 2 disease or the less severe L444P mutation associated with type 3 disease. Mice homozygous for the RecNciI mutation had little GC enzyme activity and accumulated glucosylceramide in brain and liver. In contrast, the mice homozygous for the L444P mutation had higher levels of GC activity and no detectable accumulation of glucosylceramide in brain and liver. Surprisingly, both point mutation mice died within 48 hr of birth, apparently of a compromised epidermal permeability barrier caused by defective glucosylceramide metabolism in the epidermis.


Angiotensin converting enzyme expression is increased in small pulmonary arteries of rats with hypoxia-induced pulmonary hypertension.
Previous studies suggest that while lung angiotensin converting enzyme (ACE) activity is reduced during chronic hypoxia, inhibitors of ACE attenuate hypoxic pulmonary hypertension. In an attempt to explain this paradox we investigated the possibility that whole lung ACE activity may not reflect local pulmonary vascular ACE expression. The experimental approach combined in vivo hemodynamic studies in control and chronically hypoxic rats, measurement of whole lung ACE activity, and evaluation of local pulmonary vascular ACE expression by in situ hybridization and immunohistochemistry. Total lung ACE activity was reduced to 50% of control activity by 5 d of hypoxia and remained low for the duration of the study. Immunohistochemistry showed a marked reduction of ACE staining in alveolar capillary endothelium. However, an increase in ACE staining was observed in the walls of small newly muscularized pulmonary arteries at the level of alveolar ducts and walls. In situ hybridization studies showed increased signal for ACE mRNA in the same vessels. Inhibition of ACE by captopril during chronic hypoxia attenuated pulmonary hypertension and markedly reduced distal muscularization of small pulmonary arteries. In addition, we demonstrated marked longitudinal variation in ACE expression along the normal pulmonary vasculature with the highest levels found in small muscular arteries associated with terminal and respiratory bronchioles. We conclude that local ACE expression is increased in the walls of small pulmonary arteries during the development of hypoxic pulmonary hypertension, despite a generalized reduction in alveolar capillary ACE expression, and we speculate that local arteriolar ACE may play a role in the vascular remodeling associated with pulmonary hypertension.


Organizational characteristics and processes are important in the adoption of the Alberta Nutrition Guidelines for Children and Youth in child-care centres.
The objective of the present study was to gain an understanding of the organizational characteristics and processes in two child-care centres that may influence adoption of the Alberta Nutrition Guidelines for Children and Youth (ANGCY). In-depth qualitative case studies. Data were collected through direct observations, key informant interviews and field notes. Diffusion of Innovations theory guided the evaluation and intrinsic case analysis. Two urban child-care centres in Edmonton, Alberta, Canada identified as exemplary early adopter cases. Ten key informants comprised of directors, junior and senior staff members participated in interviews. Organizational processes such as leadership, networking and knowledge brokering, health champions and organizational culture positively influenced adoption behaviour in child-care centres. A key determinant influencing organizational behaviour within both centres was the directors' strong leadership. Acceptance of and adherence to the guidelines were facilitated by organizational factors, such as degree of centralization, formalization and complexity, level of staff training and education. Knowledge brokering by directors was important for transferring and exchanging information across the centre. All child-care staff embraced their informal role as health champions as essential to supporting guideline adherence and encouraging healthy food and eating environments. Organizational processes and characteristics such as leadership, knowledge brokering and networking, organizational culture and health champions played an important role in the adoption of nutrition guidelines in child-care centres. The complex interplay of decision making, organization of work and specialization of roles influenced the extent to which nutrition guidelines were adopted.


Cost-effectiveness analysis of general anaesthesia versus local anaesthesia for carotid surgery (GALA Trial).
Health outcomes and costs are both important when deciding whether general (GA) or local (LA) anaesthesia should be used during carotid endarterectomy. The aim of this study was to assess the cost-effectiveness of carotid endarterectomy under LA or GA in patients with symptomatic or asymptomatic carotid stenosis for whom surgery was advised. Using patient-level data from a large, multinational, randomized controlled trial (GALA Trial) time free from stroke, myocardial infarction or death, and costs incurred were evaluated. The cost-effectiveness outcome was incremental cost per day free from an event, within a time horizon of 30 days. A patient undergoing carotid endarterectomy under LA incurred fewer costs (mean difference pound178) and had a slightly longer event-free survival (difference 0.16 days, but the 95 per cent confidence limits around this estimate were wide) compared with a patient who had GA. Existing uncertainty did not have a significant impact on the decision to adopt LA, over a wide range of willingness-to-pay values. If cost-effectiveness was considered in the decision to adopt GA or LA for carotid endarterectomy, given the evidence provided by this study, LA is likely to be the favoured treatment for patients for whom either anaesthetic approach is clinically appropriate.


Do systemic risk factors impact invasive findings from virtual histology? Insights from the international virtual histology registry.
Cardiovascular risk factors such as elevated serum lipid levels are important in the development of coronary atherosclerosis. Radiofrequency (RF) analysis of intravascular ultrasound [IVUS, Virtual histology (VH)] offers a unique tool to study the composition of coronary atherosclerotic plaque in vivo. We used data from the multicentre VH registry to assess the association between cardiovascular risk factors and coronary plaque volume and composition. Between August 2004 and July 2006, 990 patients in 42 centres were enrolled in a prospective, multicentre, non-randomized global VH registry. Coronary artery imaging was performed by conventional IVUS and RF-IVUS. The four RF-IVUS plaque components [dense calcium (DC), necrotic core (NC), fibrous (F) tissue, and fibro fatty (FF)] were analysed in every recorded frame. The results were expressed as mean cross-sectional areas, absolute volume, and percentage of total plaque volume. Risk factor assessment included evaluation of family history of previous myocardial infarction (MI), past or current smoking, diabetes mellitus, hypertension, and the laboratory measurements. Patients with diabetes had an increased relative proportion of NC (6.47 +/- 0.28 vs. 5.86 +/- 0.14%, P = 0.037) and DC (4.58 +/- 0.27 vs. 3.90 +/- 0.14%, P = 0.017), and patients with hypertension had an increased relative proportion of FF, DC (4.35 +/- 0.16 vs. 3.57 +/- 0.17%, P = 0.02) and NC (6.24 +/- 0.17 vs. 5.60 +/- 0.19%, P = 0.01). Compared with patients with LDL-C <100 mg/dL, patients with LDL-C >160 mg/dL had higher plaque volume (342.1 +/- 26.2 vs. 318.6 +/- 10.7 mm(3)). Linear regression analysis showed a correlation between the level of HDL-C and F (r = -0.149, P < 0.01), FF (r = -0.106, P < 0.01), and NC (r = -0.90, P < 0.05). The level of LDL correlated with F (r = 0.110, P < 0.01). Patients with prior MI have an increased percentage of F (30.03 +/- 0.59 vs. 28.20 +/- 0.37%, P = 0.009). Smoking had no relevant effect on plaque composition. Treatment with acetylsalicylacid and statins reduced FF with altering plaque volume. Radiofrequency-IVUS detects marked differences in coronary plaque composition related to the risk factor profile with particular focus on lipid levels. Greater amounts of NC were associated with diabetes, hypertension, MI, and low HDL-C. The effects of treatment of changes related to plaque composition are underway.


Statistical inference for net benefit measures in biomarker validation studies.
Referral strategies based on risk scores and medical tests are commonly proposed. Direct assessment of their clinical utility requires implementing the strategy and is not possible in the early phases of biomarker research. Prior to late-phase studies, net benefit measures can be used to assess the potential clinical impact of a proposed strategy. Validation studies, in which the biomarker defines a prespecified referral strategy, are a gold standard approach to evaluating biomarker potential. Uncertainty, quantified by a confidence interval, is important to consider when deciding whether a biomarker warrants an impact study, does not demonstrate clinical potential, or that more data are needed. We establish distribution theory for empirical estimators of net benefit and propose empirical estimators of variance. The primary results are for the most commonly employed estimators of net benefit: from cohort and unmatched case-control samples, and for point estimates and net benefit curves. Novel estimators of net benefit under stratified two-phase and categorically matched case-control sampling are proposed and distribution theory developed. Results for common variants of net benefit and for estimation from right-censored outcomes are also presented. We motivate and demonstrate the methodology with examples from lung cancer research and highlight its application to study design.


A molecular mechanism realizing sequence-specific recognition of nucleic acids by TDP-43.
TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein containing two consecutive RNA recognition motifs (RRM1 and RRM2) in tandem. Functional abnormality of TDP-43 has been proposed to cause neurodegeneration, but it remains obscure how the physiological functions of this protein are regulated. Here, we show distinct roles of RRM1 and RRM2 in the sequence-specific substrate recognition of TDP-43. RRM1 was found to bind a wide spectrum of ssDNA sequences, while no binding was observed between RRM2 and ssDNA. When two RRMs are fused in tandem as in native TDP-43, the fused construct almost exclusively binds ssDNA with a TG-repeat sequence. In contrast, such sequence-specificity was not observed in a simple mixture of RRM1 and RRM2. We thus propose that the spatial arrangement of multiple RRMs in DNA/RNA binding proteins provides steric effects on the substrate-binding site and thereby controls the specificity of its substrate nucleotide sequences.


The skin as a social organ.
In general, social neuroscience research tends to focus on visual and auditory channels as routes for social information. However, because the skin is the site of events and processes crucial to the way we think about, feel about, and interact with one another, touch can mediate social perceptions in various ways. This review situates cutaneous perception within a social neuroscience framework by discussing evidence for considering touch (and to some extent pain) as a channel for social information. Social information conveys features of individuals or their interactions that have potential bearing on future interactions, and attendant mental and emotional states. Here, we discuss evidence for an affective dimension of touch and explore its wider implications for the exchange of social information. We consider three important roles for this affective dimension of the cutaneous senses in the transmission and processing of social information: first, through affiliative behavior and communication; second, via affective processing in skin-brain pathways; and third, as a basis for intersubjective representation.


Radiative effects of global MODIS cloud regimes.
We update previously published MODIS global cloud regimes (CRs) using the latest MODIS cloud retrievals in the Collection 6 dataset. We implement a slightly different derivation method, investigate the composition of the regimes, and then proceed to examine several aspects of CR radiative appearance with the aid of various radiative flux datasets. Our results clearly show the CRs are radiatively distinct in terms of shortwave, longwave and their combined (total) cloud radiative effect. We show that we can clearly distinguish regimes based on whether they radiatively cool or warm the atmosphere, and thanks to radiative heating profiles to discern the vertical distribution of cooling and warming. Terra and Aqua comparisons provide information about the degree to which morning and afternoon occurrences of regimes affect the symmetry of CR radiative contribution. We examine how the radiative discrepancies among multiple irradiance datasets suffering from imperfect spatiotemporal matching depend on CR, and whether they are therefore related to the complexity of cloud structure, its interpretation by different observational systems, and its subsequent representation in radiative transfer calculations.


Genetic Factors Influencing Coagulation Factor XIII B-Subunit Contribute to Risk of Ischemic Stroke.
Abnormal coagulation has been implicated in the pathogenesis of ischemic stroke, but how this association is mediated and whether it differs between ischemic stroke subtypes is unknown. We determined the shared genetic risk between 14 coagulation factors and ischemic stroke and its subtypes. Using genome-wide association study results for 14 coagulation factors from the population-based TwinsUK sample (N≈2000 for each factor), meta-analysis results from the METASTROKE consortium ischemic stroke genome-wide association study (12 389 cases, 62 004 controls), and genotype data for 9520 individuals from the WTCCC2 ischemic stroke study (3548 cases, 5972 controls-the largest METASTROKE subsample), we explored shared genetic risk for coagulation and stroke. We performed three analyses: (1) a test for excess concordance (or discordance) in single nucleotide polymorphism effect direction across coagulation and stroke, (2) an estimation of the joint effect of multiple coagulation-associated single nucleotide polymorphisms in stroke, and (3) an evaluation of common genetic risk between coagulation and stroke. One coagulation factor, factor XIII subunit B (FXIIIB), showed consistent effects in the concordance analysis, the estimation of polygenic risk, and the validation with genotype data, with associations specific to the cardioembolic stroke subtype. Effect directions for FXIIIB-associated single nucleotide polymorphisms were significantly discordant with cardioembolic disease (smallest P=5.7×10(-04)); the joint effect of FXIIIB-associated single nucleotide polymorphisms was significantly predictive of ischemic stroke (smallest P=1.8×10(-04)) and the cardioembolic subtype (smallest P=1.7×10(-04)). We found substantial negative genetic covariation between FXIIIB and ischemic stroke (rG=-0.71, P=0.01) and the cardioembolic subtype (rG=-0.80, P=0.03). Genetic markers associated with low FXIIIB levels increase risk of ischemic stroke cardioembolic subtype.


A new reduction technique for completely displaced forearm and wrist fractures in children: a biomechanical assessment and 4-year clinical evaluation.
Most pediatric distal radius fractures are treated with closed methods, however, in recent years an increasing number of fractures are treated with operative management. Multiple reduction techniques are described in the orthopaedic literature but no recent advances have been made in the closed management of these injuries. We describe the efficacy of new, single-provider manual reduction technique that improves reduction efficacy and we separately show its biomechanical superiority to other common techniques. Review the results of a new reduction technique, known as the Lower Extremity-aided Fracture Reduction (LEAFR) maneuver, used on a specific cohort of consecutively treated patients at a single institution over a 4-year period with bayoneted distal radius fractures. Intention-to-treat methodology and descriptive statistics are utilized to analyze accuracy of reduction, need for operative intervention, residual deformity, and complications. In addition, perform a biomechanical comparison between the LEAFR maneuver, the 2 person traction counter-traction method and finger traps. The technique allowed 24 consecutively treated, bayoneted distal radius fractures to be reduced from average translational and shortening deformities of 11.4 and 6.5 mm to 2.1 and 0.4 mm, respectively (P<0.0001). Two (8%) of the 24 patients had failure to eliminate bayonet displacement, whereas only 3 patients (12.5%) ultimately required operative intervention. No cases of growth arrest were noted. A biomechanical assessment of the maneuver showed the ability to generate an average of 597.8 Newtons (N) of axial traction which is statistically significant in comparison to other accepted methods of reduction. The LEAFR is a clinically effective and biomechanically sound technique for reduction of bayoneted distal radius fractures in children. It is a simple, reproducible technique not reliant on equipment or additional skilled providers. In addition, it results in decreased rates of operative management and represents advancement in the treatment of pediatric distal radius fractures. Level IV (Retrospective Case Series), Level I (Biomechanical Comparison Study).


Interpreting the process behind endemism in China by integrating the phylogeography and ecological niche models of the Stachyridopsis ruficeps.
An area of endemism (AOE) is a complex expression of the ecological and evolutionary history of a species. Here we aim to address the principal drivers of avian diversification in shaping patterns of endemism in China by integrating genetic, ecological, and distributional data on the Red-headed Tree Babbler (Stachyridopsis ruficeps), which is distributed across the eastern Himalayas and south China. We sequenced two mtDNA markers from 182 individuals representing all three of the primary AOEs in China. Phylogenetic inferences were used to reconstruct intraspecific phylogenetic relationships. Divergence time and population demography were estimated to gain insight into the evolutionary history of the species. We used Ecological niche modeling to predict species' distributions during the Last Glacial Maximum (LGM) and in the present. Finally, we also used two quantitative tests, an identity test and background test to assess the similarity of ecological niche preferences between adjacent lineages. We found five primary reciprocally monophyletic clades, typically separated approximately 0.2-2.27 MYA, of which three were deeply isolated endemic lineages located in the three AOEs. All phylogroups were detected to have undergone population expansion during the past 0.3 MY. Niche models showed discontinuous habitats, and there were three barriers of less suitable habitat during the LGM and in modern times. Ecoclimatic niches may diverge significantly even over recent timescales, as each phylogroup had a unique distribution, and unique niche characteristics. Vicariant events associated with geographical and ecological barriers, glacial refuges and ecological differentiation may be the main drivers forming the pattern of endemism in China.


Vitamin A enhances antitumor effect of a green tea polyphenol on melanoma by upregulating the polyphenol sensing molecule 67-kDa laminin receptor.
Green tea consumption has been shown to have cancer preventive qualities. Among the constituents of green tea, (-)-Epigallocatechin-3-O-gallate (EGCG) is the most effective at inhibiting carcinogenesis. However, the concentrations of EGCG that are required to elicit the anticancer effects in a variety of cancer cell types are much higher than the peak plasma concentration that occurs after drinking an equivalent of 2-3 cups of green tea. To obtain the anticancer effects of EGCG when consumed at a reasonable concentration in daily life, we investigated the combination effect of EGCG and food ingredient that may enhance the anticancer activity of EGCG on subcutaneous tumor growth in C57BL/6N mice challenged with B16 melanoma cells. All-trans-retinoic acid (ATRA) enhanced the expression of the 67-kDa laminin receptor (67LR) and increased EGCG-induced cell growth inhibition in B16 melanoma cells. The cell growth inhibition seen with the combined EGCG and ATRA treatment was abolished by treatment with an anti-67LR antibody. In addition, the combined EGCG and ATRA treatment significantly suppressed the melanoma tumor growth in mice. Expression of 67LR in the tumor increased upon oral administration of ATRA or a combined treatment of EGCG and ATRA treatment. Furthermore, RNAi-mediated silencing of the retinoic acid receptor (RAR) alpha attenuated the ATRA-induced enhancement of 67LR expression in the melanoma cells. An RAR agonist enhanced the expression levels of 67LR and increased EGCG-induced cell growth inhibition. Our findings provide a molecular basis for the combination effect seen with dietary components, and indicate that ATRA may be a beneficial food component for cancer prevention when combined with EGCG.


1H NMR and UPLC-MS(E) statistical heterospectroscopy: characterization of drug metabolites (xenometabolome) in epidemiological studies.
Statistical HeterospectroscopY (SHY) is a statistical strategy for the coanalysis of multiple spectroscopic data sets acquired in parallel on the same samples. This method operates through the analysis of the intrinsic covariance between signal intensities in the same and related molecular fingerprints measured by multiple spectroscopic techniques across cohorts of samples. Here, the method is applied to 600-MHz (1)H NMR and UPLC-TOF-MS (E) data obtained from human urine samples ( n = 86) from a subset of an epidemiological population unselected for any relevant phenotype or disease factor. We show that direct cross-correlation of spectral parameters, viz. chemical shifts from NMR and m/ z data from MS, together with fragment analysis from MS (E) scans, leads not only to the detection of numerous endogenous urinary metabolites but also the identification of drug metabolites that are part of the latent use of drugs by the population. We show previously unreported positive mode ions of ibuprofen metabolites with their NMR correlates and suggest the detection of new metabolites of disopyramide in the population samples. This approach is of great potential value in the description of population xenometabolomes and in population pharmacology studies, and indeed for drug metabolism studies in general.