Malignancy and mortality in paediatric-onset inflammatory bowel disease: a 3-year prospective, multinational study from the paediatric IBD Porto group of ESPGHAN.
Risk benefit strategies in managing inflammatory bowel diseases (IBD) are dependent upon understanding the risks of uncontrolled inflammation vs those of treatments. Malignancy and mortality in IBD have been associated with disease-related inflammation and immune suppression, but data are limited due to their rare occurrence. To identify and describe the most common causes of mortality, types of cancer and previous or current therapy among children and young adults with paediatric-onset IBD. Information on paediatric-onset IBD patients diagnosed with malignancy or mortality was prospectively collected via a survey in 25 countries over a 42-month period. Patients were included if death or malignancy occurred after IBD diagnosis but before the age of 26 years. In total, 60 patients were identified including 43 malignancies and 26 fatal cases (9 due to cancer). Main causes of fatality were malignancies (n = 9), IBD or IBD-therapy related nonmalignant causes (n = 10; including 5 infections), and suicides (n = 3). Three cases, all fatal, of hepatosplenic T-cell lymphoma were identified, all were biologic-naïve but thiopurine-exposed. No other haematological malignancies were fatal. The 6 other fatal cancer cases included 3 colorectal adenocarcinomas and 3 cholangiocarcinomas (CCAs). Primary sclerosing cholangitis (PSC) was present in 5 (56%) fatal cancers (1 colorectal carcinoma, 3 CCAs and 1 hepatosplenic T-cell lymphoma). We report the largest number of paediatric-onset IBD patients with cancer and/or fatal outcomes to date. Malignancies followed by infections were the major causes of mortality. We identified PSC as a significant risk factor for cancer-associated mortality. Disease-related adenocarcinomas were a commoner cause of death than lymphomas.


Healthcare resource utilization and costs in patients with multiple myeloma with and without skeletal-related events.
To compare healthcare resource use and costs between newly diagnosed multiple myeloma (NDMM) patients with and without skeletal-related events (SREs). Adults newly diagnosed with MM (1 January 2006 and 30 June 2017) with at least 12 months continuous health coverage prior to diagnosis were identified using the IBM MarketScan administrative claims. To control for baseline differences, NDMM patients with SREs were propensity score matched to NDMM patients without SREs. Outcomes included annual HRU and costs during follow-up along with number and type of SREs (SRE cohort only). Patients with SREs were stratified by number of SREs, and annual SRE-related costs were reported. Student's t test and Chi-squared test were used to compare outcomes. Before matching, the 6648 patients in the SRE cohort had more comorbidities, were more likely to have MM treatment, and had higher pre-index healthcare costs than the 7458 patients in the non-SRE cohort. After matching, cohorts of 3432 patients were well balanced on baseline characteristics. Patients with SREs (vs. without SREs) had significantly higher inpatient, outpatient, and pharmacy HRU. Patients with SREs had significantly higher mean annual all-cause healthcare costs ($213,361 vs. $94,896, p < 0.001) with hospitalization being the leading driver of increased costs (38.7% of total). Among 6648 patients with SREs, the mean annual SRE-related healthcare costs were $39,603, $45,463, and $50,111 for patients with one, two, and three or more events, respectively. NDMM patients with SREs have more than twice the all-cause healthcare costs than matched patients without SREs. Costs increase with the number of SRE events.


The effect of intensified extracorporeal photochemotherapy on long-term survival in patients with severe acute graft-versus-host disease.
Acute graft-versus-host disease (GVHD) is a major cause of mortality after allogeneic hematopoietic stem cell transplantation. We performed a phase II study on patients with acute steroid-refractory GVHD grades II to IV given extracorporeal photochemotherapy (ECP) weekly and analyzed response and long-term survival. Complete resolution of GVHD was achieved in 82% of patients with cutaneous involvement, 61% with liver involvement, and 61% with gut involvement. The probability of survival was 59% among patients who responded completely to ECP compared to 11% in patients not responding completely. We conclude that intensified ECP is highly effective in acute GVHD and that sustained responses are associated with over 50% long-term survival.


Electromagnetic field exposure assessment in Europe radiofrequency fields (10 MHz-6 GHz).
Average levels of exposure to radiofrequency (RF) electromagnetic fields (EMFs) of the general public in Europe are difficult to summarize, as exposure levels have been reported differently in those studies in which they have been measured, and a large proportion of reported measurements were very low, sometimes falling below detection limits of the equipment used. The goal of this paper is to present an overview of the scientific literature on RF EMF exposure in Europe and to characterize exposure within the European population. A comparative analysis of the results of spot or long-term RF EMF measurements in the EU indicated that mean electric field strengths were between 0.08 V/m and 1.8 V/m. The overwhelming majority of measured mean electric field strengths were <1 V/m. It is estimated that <1% were above 6 V/m and <0.1% were above 20 V/m. No exposure levels exceeding European Council recommendations were identified in these surveys. Most population exposures from signals of radio and television broadcast towers were observed to be weak because these transmitters are usually far away from exposed individuals and are spatially sparsely distributed. On the other hand, the contribution made to RF exposure from wireless telecommunications technology is continuously increasing and its contribution was above 60% of the total exposure. According to the European exposure assessment studies identified, three population exposure categories (intermittent variable partial body exposure, intermittent variable low-level whole-body (WB) exposure and continuous low-level WB exposure) were recognized by the authors as informative for possible future risk assessment.


Simulation study of spatial resolution and sensitivity for the tapered depth of interaction PET detectors for small animal imaging.
Improvements to current small animal PET scanners can be made by improving the sensitivity and the spatial resolution of the scanner. In the past, efforts have been made to minimize the crystal dimensions in the axial and transaxial directions to improve the spatial resolution and to increase the crystal length to improve the sensitivity of the scanner. We have designed tapered PET detectors with the purpose of reducing the gaps between detector modules and optimizing the sensitivity of a future-generation small animal PET scanner. In this work, we investigate spatial resolution and sensitivity of a scanner based on tapered detector elements using Monte Carlo simulations. For tapered detector elements more scintillation material is used per detector resulting in a higher sensitivity of the scanner. However, since the detector elements are not uniform in size, degradation in spatial resolution is also expected. To investigate characteristics of tapered PET detectors, the spatial resolution and sensitivity of a one-ring scanner were simulated for a system based on traditional cuboid detectors and a scanner based on tapered detectors. Additionally, the effect of depth of interaction (DOI) resolution on the spatial resolution for the traditional and tapered detectors was evaluated. All simulations were performed using the Monte Carlo simulation package GATE. Using the tapered arrays, a 64% improvement in the sensitivity across the field of view was found compared with traditional detectors for the same ring diameter. The level of DOI encoding was found to be the dominating factor in determining the radial spatial resolution and not the detector shape. For all levels of DOI encoding, no significant difference was found for the spatial resolution when comparing the tapered and the cuboid detectors. Detectors employing the tapered crystal design along with excellent DOI resolution will lead to PET scanners with higher sensitivity and uniform spatial resolution across the field of view.


Coupled object detection and tracking from static cameras and moving vehicles.
We present a novel approach for multi-object tracking which considers object detection and spacetime trajectory estimation as a coupled optimization problem. Our approach is formulated in a Minimum Description Length hypothesis selection framework, which allows it to recover from mismatches and temporarily lost tracks. Building upon a state-of-the-art object detector, it performs multiview/multicategory object recognition to detect cars and pedestrians in the input images. The 2D object detections are checked for their consistency with (automatically estimated) scene geometry and are converted to 3D observations which are accumulated in a world coordinate frame. A subsequent trajectory estimation module analyzes the resulting 3D observations to find phyically plausible spacetime trajectories. Tracking is achieved by performing model selection after every frame. At each time instant, our approach searches for the globally optimal set of spacetime trajectories which provides the best explanation for the current image and for all evidence collected so far, while satisfying the constraints that no two objects may occupy the same physical space, nor explain the same image pixels at any point in time. Successful trajectory hypotheses are then fed back to guide object detection in future frames. The optimization procedure is kept efficient throught incremental computation and conservative hypothesis pruning. We evaluate our approach on several challenging video sequences and demonstrate its performance on both a surveillance-type scenario and a scenario where the input videos are taken from inside a moving vehicle passing through crowded city areas.


Multimetal accumulation in crustaceans in surface water related to body size and water chemistry.
Many relationships of bioaccumulation of metals have been derived in the past, but verification in the field is often lacking. In the present study, the authors collected field data on bioaccumulation in caged Daphnia magna and Gammarus roeseli in 12 different contaminated brooks. Besides generating a comprehensive data set on bioaccumulation for these species, the authors also checked whether the bioavailability at the biotic ligand is useful to explain differences in observed bioaccumulation. Increasing bioaccumulation of Mn, Cd, Co, and Ni was observed, which leveled off at higher concentrations. Whole-body concentrations of Ca, Na, Mg, K, Fe, Cu, Se, and Zn were independent of exposure concentrations. Univariate and multivariate regressions were performed to examine the relationships between accumulated metals and dissolved metal concentrations (C(w) ), fractional occupancy of the biotic ligand (f(BL) ), species weight, and other undefined species traits. Significant relations between body weight and bioaccumulation were found for Na, Fe, Mn, Cd, Co, and Zn; smaller organisms accumulated larger amounts of these elements. Reduced body weight was accompanied by elevated concentrations of Co, Cu, and Fe in D. magna and elevated concentrations of Mn in G. roeseli, indicating toxicity. Although significant relations were found between bioaccumulation and f(BL) for Mn and Co, C(w) was a better predictor of bioaccumulation.


Synthesis and in vitro evaluation of tetrahydroisoquinolines with pendent aromatics as sigma-2 (σ2) selective ligands.
5-Bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxybenzamide 1 is a potent and selective σ2 receptor ligand suitable for further development. A series of new analogues, incorporating a variety of isoquinoline and carboxylic acid moieties, linked together with either a linear or cyclic amine spacer have been synthesised and assessed for their σ1/σ2 binding affinity and selectivity. Compounds with a rigid piperidine spacer gave Ki values for the σ2 receptor between 8.7-845 nM. Changing the configuration of the methoxy groups on the isoquinoline moiety resulted in molecules with σ2Ki values of 4.4-133 nM whereas varying the length and flexibility of the carbon spaces gave σ2Ki values 0.88-15.0 nM, some of the most active, selective σ2 ligands to date. Thus, the flexibility and length of the carbon linker and the carboxylic acid moiety are confirmed to be key to the exceptional binding affinity and selectivity for this active series. Additionally, the incorporation of a halogen on selected carboxylic acid moieties provided a convenient strategy for the introduction of a radiohalogen for applications in pharmacological and imaging studies.


Performance, health and physiological responses of newly weaned feedlot cattle supplemented with feed-grade antibiotics or alternative feed ingredients.
With increased regulations regarding the use of feed-grade antimicrobials in livestock systems, alternative strategies to enhance growth and immunity of feedlot cattle are warranted. Hence, this experiment compared performance, health and physiological responses of cattle supplemented with feed-grade antibiotics or alternative feed ingredients during the initial 60 days in the feedlot. Angus×Hereford calves (63 steers+42 heifers) originating from two cow-calf ranches were weaned on day -3, obtained from an auction yard on day -2 and road-transported (800 km; 12 h) to the feedlot. Upon arrival on day -1, shrunk BW was recorded. On day 0, calves were ranked by sex, source and shrunk BW, and allocated to one of 21 pens. Pens were assigned to receive (7 pens/treatment) a free-choice total mixed ration containing: (1) lasalocid (360 mg/calf daily of Bovatec; Zoetis, Florham Park, NJ, USA)+chlortetracycline (350 mg/calf of Aureomycin at cycles of 5-day inclusion and 2-day removal from diet; Zoetis) from days 0 to 32, and monensin only (360 mg/calf daily of Rumensin; Elanco Animal Health, Greenfield, IN, USA) from days 33 to 60 (PC), (2) sodium saccharin-based sweetener (Sucram at 0.04 g/kg of diet dry matter; Pancosma SA; Geneva, Switzerland)+plant extracts containing eugenol, cinnamaldehyde and capsicum (800 mg/calf daily of XTRACT Ruminants 7065; Pancosma SA) from days 0 to 32 and XTRACT only (800 mg/calf daily) from days 33 to 60 (EG) or (3) no supplemental ingredients (CON; days 0 to 60). Calves were assessed for bovine respiratory disease (BRD) signs and dry matter intake was recorded from each pen daily. Calves were vaccinated against BRD pathogens on days 0 and 22. Shrunk BW was recorded on day 61, and blood samples collected on days 0, 6, 11, 22, 33, 43 and 60. Calf ADG was greater (P=0.04) in PC v. EG and tended (P=0.09) to be greater in PC v. CON. Feed efficiency also tended (P=0.09) to be greater in PC v. CON, although main treatment effect for this response was not significant (P=0.23). Mean serum titers against bovine respiratory syncytial virus were greater in EG v. PC (P=0.04) and CON (tendency; P=0.08). Collectively, the inclusion of alternative feed ingredients prevented the decrease in feed efficiency when chlortetracycline and ionophores were not added to the initial feedlot diet, and improved antibody response to vaccination against the bovine respiratory syncytial virus in newly weaned cattle.


Subcellular Localization of Class I Histone Deacetylases in the Developing Xenopus tectum.
Histone deacetylases (HDACs) are thought to localize in the nucleus to regulate gene transcription and play pivotal roles in neurogenesis, apoptosis, and plasticity. However, the subcellular distribution of class I HDACs in the developing brain remains unclear. Here, we show that HDAC1 and HDAC2 are located in both the mitochondria and the nucleus in the Xenopus laevis stage 34 tectum and are mainly restricted to the nucleus following further brain development. HDAC3 is widely present in the mitochondria, nucleus, and cytoplasm during early tectal development and is mainly distributed in the nucleus in stage 45 tectum. In contrast, HDAC8 is broadly located in the mitochondria, nucleus, and cytoplasm during tectal development. These data demonstrate that HDAC1, HDAC2, and HDAC3 are transiently localized in the mitochondria and that the subcellular distribution of class I HDACs in the Xenopus tectum is heterogeneous. Furthermore, we observed that spherical mitochondria accumulate in the cytoplasm at earlier stages, whereas elongated mitochondria are evenly distributed in the tectum at later stages. The activity of histone acetylation (H4K12) remains low in mitochondria during tectal development. Pharmacological blockades of HDACs using a broad spectrum HDAC inhibitor of Trichostatin A (TSA) or specific class I HDAC inhibitors of MS-275 and MGCD0103 decrease the number of mitochondria in the tectum at stage 34. These findings highlight a link between the subcellular distribution of class I HDACs and mitochondrial dynamics in the developing optic tectum of Xenopus laevis.


1,2,3-Triazolyl ester of ketorolac (15K), a potent PAK1 blocker, inhibits both growth and metastasis of orthotopic human pancreatic cancer xenografts in mice.
More than 90% of human pancreatic cancers carry the oncogenic mutant of Ki-RAS and their growth depends on its downstream kinase PAK1, mainly because PAK1 blocks the apoptosis of cancer cells selectively. We developed a highly cell-permeable PAK1-blocker called 15K from an old pain-killer (ketorolac), that is shown here to inhibit the growth of three pancreatic cancer cell lines with IC50 values ranging 41-88 nM in vitro. The anti-cancer effect of 15K was further investigated in an orthotopic xenograft model with gemcitabine (GEM)-resistant human pancreatic cancer cell lines (AsPC-1 and BxPC-3) expressing luciferase in athymic mice. During 4 weeks, 15K blocks total burden (growth) of both AsPC-1 and BxPC-3 tumors (measured as radians/sec) with the IC50 below daily dose of 0.1 mg/kg, i.p. In a similar manner 15K reduced both their invasion and metastases as well, while it had no effect on either body weight or hematological parameters even at 5 mg/kg/day. To the best of our knowledge, 15K is so far the most potent among synthetic PAK1-blockers in vivo, and could be potentially useful for therapy of GEM-resistant cancers.


Comparison of the burden of anorexia nervosa in the Middle East and North Africa region between 1990 and 2019.
Anorexia nervosa (AN) is a complex and heritable psychiatric disorder, which imposes significant mortality and morbidity on sufferers globally. We aimed to report the prevalence, incidence and disability-adjusted life-years (DALYs) attributable to AN in the Middle East and North Africa (MENA) region by age, sex and socio-demographic index (SDI), between 1990 and 2019. The disease burden attributable to AN was obtained for the 21 countries located in the MENA region between 1990 and 2019 using publicly available data from the Global Burden of Disease (GBD) 2019 study. All estimates were provided as counts and age-standardized rates per 100,000 population, along with 95% uncertainty intervals (UIs). In 2019, the estimated age-standardised point prevalence and incidence rate of AN (per 100,000) in MENA were 49.3 (95% UI: 34.6-70.4) and 16.0 (11.3-22.0), which were 11.4% (7.3-15.4) and 5.9% (2.6-9.1) higher than in 1990, respectively. Furthermore, the regional age-standardised DALY rate was 10.6 (6.3-17.0) per 100,000 in 2019, which was 11.8% (5.2-19.1) higher than in 1990. In 2019, Kuwait [17.3 (10.3-27.9)] and Afghanistan [6.3 (3.7-10.3)] had the highest and lowest age-standardised DALY rates, respectively. In addition, Iran showed the largest increases in the age-standardised point prevalence [30.0% (24.1-36.2)], incidence [24.6% (18.6-30.4)] and DALY [30.5% (22.6-38.9)] rates between 1990 and 2019. In 2019, the number of prevalent cases and prevalence estimates peaked in the 15-19 age group for males and the 20-24 age group for females, with females having a higher number of cases and prevalence in all age groups. In 2019, the age-standardised DALY rates in MENA were higher than the global rates among males aged 10-34 years, but were lower than the global estimates among females in almost all age groups. In addition, the burden of AN was positively associated with the level of socio-economic development during the measurement period. The burden of AN in the MENA region increased between 1990 and 2019, which indicates that it is likely to become a more serious public health issue in the future. Up-to-date information about the epidemiological trends in the region would allow health policymakers to make informed and appropriate decisions to help address this issue. The findings of the present study showed that the point prevalence and incidence rate of anorexia nervosa have increased in the Middle East and North Africa region between 1990 and 2019. The highest burden in 2019 was found in Kuwait, while Afghanistan had the lowest attributable burden. In addition, between 1990 and 2019 Iran had the largest increase in the point prevalence of anorexia nervosa. Also in 2019, anorexia nervosa was more prevalent in females and peaked in the 15-19 age group for males and the 20-24 age group for females. Furthermore, as the level of socioeconomic development increased, so did the burden attributable to anorexia nervosa.


Sleep and circadian rhythm disruption and recognition memory in schizophrenia.
Schizophrenia patients often show irregularities in sleep and circadian rhythms and deficits in recognition memory. Similar phenotypes are seen in schizophrenia-relevant genetic mouse models, such as synaptosomal associated protein of 25 kDa (Snap-25) point mutant mice, vasoactive intestinal peptide receptor 2 (Vipr2) knockout mice, and neuregulin 1 (Nrg1)-deficient mice. Sleep and circadian abnormalities and impaired recognition memory may be causally related in both schizophrenia patients and schizophrenia-relevant mouse models, since sleep deprivation, abnormal photic input, and the manipulation of core clock genes (cryptochrome 1/2) can all disrupt object recognition memory in rodent models. The recognition deficits observed in patients and mouse models (both schizophrenia-related and -unrelated) are discussed here in terms of the dual-process theory of recognition, which postulates that there are two recognition mechanisms-recollection versus familiarity-that can be selectively impaired by brain lesions, neuropsychiatric conditions, and putatively, sleep and circadian rhythm disruption. However, based on this view, the findings from patient studies and studies using genetic mouse models (Nrg1 deficiency) seem to be inconsistent with each other. Schizophrenia patients are impaired at recollection (and to a lesser extent, familiarity judgments), but Nrg1-deficient mice are impaired at familiarity-based object recognition, raising concerns regarding the validity of using these genetically modified mice to model recognition phenotypes observed in patients. This issue can be resolved in future animal studies by examining performance in different variants of the spontaneous recognition task-the standard, perirhinal cortex-dependent, object recognition task versus the hippocampus-dependent object-place recognition task-in order to see which of the two recognition mechanisms is more disrupted.


Beautification of Design Sketches Using Trainable Stroke Clustering and Curve Fitting.
We propose a new sketch parsing and beautification method that converts digitally created design sketches into beautified line drawings. Our system uses a trainable, sequential bottom-up and top-down stroke clustering method that learns how to parse input pen strokes into groups of strokes each representing a single curve, followed by point-cloud ordering that facilitates curve fitting and smoothing. This approach enables greater conceptual freedom during visual ideation activities by allowing designers to develop their sketches using multiple, casually drawn strokes without requiring them to indicate the separation between different stroke groups. With the proposed method, raw sketches are seamlessly converted into vectorized geometric models, thus, facilitating downstream assessment and editing activities.


Beyond ranking nodes: Predicting epidemic outbreak sizes by network centralities.
Identifying important nodes for disease spreading is a central topic in network epidemiology. We investigate how well the position of a node, characterized by standard network measures, can predict its epidemiological importance in any graph of a given number of nodes. This is in contrast to other studies that deal with the easier prediction problem of ranking nodes by their epidemic importance in given graphs. As a benchmark for epidemic importance, we calculate the exact expected outbreak size given a node as the source. We study exhaustively all graphs of a given size, so do not restrict ourselves to certain generative models for graphs, nor to graph data sets. Due to the large number of possible nonisomorphic graphs of a fixed size, we are limited to ten-node graphs. We find that combinations of two or more centralities are predictive (R2 scores of 0.91 or higher) even for the most difficult parameter values of the epidemic simulation. Typically, these successful combinations include one normalized spectral centrality (such as PageRank or Katz centrality) and one measure that is sensitive to the number of edges in the graph.


Emergence of compositionally tunable nanoscale dynamical heterogeneity in model binary lipid biomembranes.
While the existence of nanoscale dynamical heterogeneity in biological membranes has been suggested to act as an active functional platform for enabling various cellular processes like signal transduction and viral or bacterial entry, it has been extremely difficult to detect the existence of such domains. Model lipid bilayer membranes have been widely used to detect such dynamical heterogeneity in order to avoid complications arising from the compositional heterogeneity of cellular membranes. However, even in model biological membranes the issue of nanoscale lipid dynamics has remained controversial and unresolved due to the difficulty of detecting the existence of such dynamical heterogeneity on the scale of 10-300 nm. Here we report direct evidence of nanoscale lipid dynamical heterogeneity in model binary lipid bilayer membranes using a combination of super-resolution stimulated emission depletion (STED) microscopy and fluorescence correlation spectroscopy (FCS). We control the phase behavior of the lipid bilayers by varying their composition and discuss how this leads to the emergence of dynamical lipid domains on the scale of 80-150 nm, which is also dependent on the lipid phase in which such dynamics are observed. Notably, our work shows that the presence of cholesterol is not required for the existence of such domains even in fluid like bilayers, as has been widely believed, and specifies the minimal conditions required for the emergence of such dynamical heterogeneity in cellular membranes. Our work will thus not only be of great significance towards understanding the nanoscale dynamic organizing principles of cellular membranes but could also be useful in understanding the dynamics of related soft matter systems and nanoparticle-cell membrane interactions.


Plasma concentration and local anesthetic activity of procaine hydrochloride following subcutaneous administration to horses.
To determine the durations of the local anesthetic effect and plasma procaine concentrations associated with 5- and 10-mg doses of procaine hydrochloride (with or without 100 microg of epinephrine) administered SC over the lateral palmar digital nerves of horses. 6 healthy adult horses. The hoof withdrawal reflex latency (HWRL) period was determined by use of a focused heat lamp before and after administration of procaine with and without epinephrine. Blood samples were collected immediately before determination of each HWRL period to assess plasma concentrations of procaine via liquid chromatography-mass spectrometry-mass spectrometry (LC-MS-MS). 10 but not 5 mg of procaine alone and 5 and 10 mg of procaine administered with epinephrine significantly prolonged the HWRL period (mean durations of effect, 5, 120 and 180 minutes, respectively), compared with baseline values. Plasma procaine concentrations did not correlate well with local anesthetic activity; for example, although the HWRL was prolonged to the maximum permitted duration of 20 seconds at 60 to 180 minutes following administration of the 5-mg dose of procaine with epinephrine in certain horses, plasma procaine concentrations were less than the limit of quantitation of the LC-MS-MS assay. Small doses of procaine coadministered with epinephrine provided long-lasting local analgesia and resulted in plasma procaine concentrations that were not always detectable via LC-MS-MS. On the basis of these results, the use of regulatory limits or thresholds for procaine concentration in equine plasma samples obtained after racing should be seriously reconsidered.


Modulation of cyclobutane thymine photodimer formation in T11-tracts in rotationally phased nucleosome core particles and DNA minicircles.
Cyclobutane pyrimidine dimers (CPDs) are DNA photoproducts linked to skin cancer, whose mutagenicity depends in part on their frequency of formation and deamination. Nucleosomes modulate CPD formation, favoring outside facing sites and disfavoring inward facing sites. A similar pattern of CPD formation in protein-free DNA loops suggests that DNA bending causes the modulation in nucleosomes. To systematically study the cause and effect of nucleosome structure on CPD formation and deamination, we have developed a circular permutation synthesis strategy for positioning a target sequence at different superhelix locations (SHLs) across a nucleosome in which the DNA has been rotationally phased with respect to the histone octamer by TG motifs. We have used this system to show that the nucleosome dramatically modulates CPD formation in a T11-tract that covers one full turn of the nucleosome helix at seven different SHLs, and that the position of maximum CPD formation at all locations is shifted to the 5΄-side of that found in mixed-sequence nucleosomes. We also show that an 80-mer minicircle DNA using the same TG-motifs faithfully reproduces the CPD pattern in the nucleosome, indicating that it is a good model for protein-free rotationally phased bent DNA of the same curvature as in a nucleosome, and that bending is modulating CPD formation.


Comparison of novel shielded nasopharynx applicator designs for intracavitary brachytherapy.
Nasopharyngeal brachytherapy is limited in part by the radiotolerance of nearby organs like the soft palate. This study explores several novel shielding designs for an intracavitary applicator to significantly reduce soft palate dose while adhering to the constraints of standard treatment procedure. The Monte Carlo code TOPAS is used to characterize each prototype under typical high-dose-rate treatment conditions. Mucosal surface dose maps are collected to evaluate the shields on their dose reduction to the central and soft palate planning points and uniformity in their shielding profile. Practicality with respect to patient comfort and pretreatment imaging is discussed. History-by-history standard deviations are calculated for each simulation. A design with elliptical tubing containing bundles of tantalum wires provides the most significant attenuation with 39% and 27% dose reduction to the center and soft palate locations, respectively. Another design utilizing miniature lead spheres loaded into a constructed cavity shows 27% and 24% dose reduction to the same locations while providing more uniform shielding and several practical benefits. Both shields are designed to be completely removable for applicator insertion and pretreatment imaging. The mean and maximum standard error of relative dose measurements was 0.36 and 1.14 percentage points, respectively. Each shielding design presented in this study provides a novel approach to safely and effectively shield healthy tissue during intracavitary nasopharyngeal brachytherapy. Analysis performed using Monte Carlo suggests that the design using metal spheres most practically shields the soft palate and should be advanced to the next stages of clinical optimization.


Are clustering effects accounted for in statistical analysis in leading dental specialty journals?
In dental research multiple site observations within patients or taken at various time intervals are commonplace. These clustered observations are not independent; statistical analysis should be amended accordingly. This study aimed to assess whether adjustment for clustering effects during statistical analysis was undertaken in five specialty dental journals. Thirty recent consecutive issues of Orthodontics (OJ), Periodontology (PJ), Endodontology (EJ), Maxillofacial (MJ) and Paediatric Dentristry (PDJ) journals were hand searched. Articles requiring adjustment accounting for clustering effects were identified and statistical techniques used were scrutinized. Of 559 studies considered to have inherent clustering effects, adjustment for this was made in the statistical analysis in 223 (39.1%). Studies published in the Periodontology specialty accounted for clustering effects in the statistical analysis more often than articles published in other journals (OJ vs. PJ: OR=0.21, 95% CI: 0.12, 0.37, p<0.001; MJ vs. PJ: OR=0.02, 95% CI: 0.00, 0.07, p<0.001; PDJ vs. PJ: OR=0.14, 95% CI: 0.07, 0.28, p<0.001; EJ vs. PJ: OR=0.11, 95% CI: 0.06, 0.22, p<0.001). A positive correlation was found between increasing prevalence of clustering effects in individual specialty journals and correct statistical handling of clustering (r=0.89). The majority of studies in 5 dental specialty journals (60.9%) examined failed to account for clustering effects in statistical analysis where indicated, raising the possibility of inappropriate decreases in p-values and the risk of inappropriate inferences.


Molecular and cytological characterization of an extra acrocentric chromosome that restores male fertility of wheat in the msH1 CMS system.
A new CMS system designated as 'msH1' has been reported in bread wheat using the cytoplasm of H. chilense. While testing this system in different wheat backgrounds, a highly fertile line with chromosome number 42 plus an extra acrocentric chromosome was obtained. The extra chromosome did not pair with any wheat chromosome at meiosis, and progeny from this line which lack the acrocentric chromosome showed pollen abortion and male sterility. In order to establish the origin of this chromosome, FISH using H. chilense genomic DNA as probe was used and showed that it had originated from H. chilense chromosome(s). The novel chromosome did not possess sequences similar to wheat rDNA; however, the probe pSc119.2 from S. cereale containing the 120 bp family was found to occur at the end of its long arm. Data obtained from FISH and EST molecular markers confirm that the long arm of the acrocentric chromosome is indeed, the short arm of chromosome 1H(ch) from H. chilense. We suggest that the novel chromosome originated from a deletion of the distal part of the long arm of chromosome 1H(ch). Neither the 1H(ch)S short arm, nor the whole chromosome 1H(ch) restores pollen fertility of the alloplasmic wheat. Therefore, the restorer gene on the acrocentric chromosome must be located on the retained segment from the hypothetical 1H(ch)L, while some pollen fertility inhibitor could be present on the deleted 1H(ch)L distal segment. Disomic addition of the acrocentric chromosome was obtained and this line resulted fully stable and fertile.


Amplitude-Integrated Electroencephalography for Early Diagnosis and Prognostic Prediction of Hypoxic Encephalopathy in Preterm Infants.
BACKGROUND The aim of this study was to analyze amplitude-integrated electroencephalography (aEEG) in early diagnosis and prognosis of hypoxic encephalopathy (HE) in premature infants. MATERIAL AND METHODS Thirty-six premature infants with HE who were treated in Linyi Central Hospital were enrolled into the study group, while 40 premature infants without HE were assigned into the control group. aEEG was conducted within 6 h after delivery to compare aEEG continuity, mature sleep-wake cycle, and maximum and minimum voltage in the 2 groups. Correlations between aEEG abnormalities and clinical grading, neurological prognosis, Apgar score, and blood gas were also analyzed among the premature infants with HE. RESULTS Compared with the control group, there were reductions in the continuous rate of aEEG, mature sleep-wake cycle, and the minimum voltage, and an increase in the maximum voltage in the study group (all P<0.05). The study group had a higher abnormal rate of aEEG and a lower normal rate of aEEG than in the control group (both P<0.05). Spearman's rank correlation coefficients for abnormal aEEG and clinical grade and poor neurological prognosis were 0.758 and 0.799, respectively. The sensitivity of abnormal aEEG in predicting severity of clinical grading was 100% with a specificity of 82.5%. The sensitivity of abnormal aEEG in predicting neurological prognosis was 100% with a specificity of 90.3%. The Apgar scores and blood glass pH of the infants with various abnormal rates of aEEG were significantly different at 1 min, 5 min, and 10 min after delivery (all P<0.05). CONCLUSIONS HE in premature infants has specific aEEG characteristics, which can be used to predict the severity and prognosis of HE.


The Rac1 regulator ELMO controls basal body migration and docking in multiciliated cells through interaction with Ezrin.
Cilia are microtubule-based organelles that are present on most cells and are required for normal tissue development and function. Defective cilia cause complex syndromes with multiple organ manifestations termed ciliopathies. A crucial step during ciliogenesis in multiciliated cells (MCCs) is the association of future basal bodies with the apical plasma membrane, followed by their correct spacing and planar orientation. Here, we report a novel role for ELMO-DOCK1, which is a bipartite guanine nucleotide exchange factor complex for the small GTPase Rac1, and for the membrane-cytoskeletal linker Ezrin, in regulating centriole/basal body migration, docking and spacing. Downregulation of each component results in ciliopathy-related phenotypes in zebrafish and disrupted ciliogenesis in Xenopus epidermal MCCs. Subcellular analysis revealed a striking impairment of basal body docking and spacing, which is likely to account for the observed phenotypes. These results are substantiated by showing a genetic interaction between elmo1 and ezrin b. Finally, we provide biochemical evidence that the ELMO-DOCK1-Rac1 complex influences Ezrin phosphorylation and thereby probably serves as an important molecular switch. Collectively, we demonstrate that the ELMO-Ezrin complex orchestrates ciliary basal body migration, docking and positioning in vivo.


A genome-wide association study reveals variants in ARL15 that influence adiponectin levels.
The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P< or =5x10(-8)). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P< or =0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2x10(-19) for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9x10(-8), n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5x10(-6), n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-3), n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.


Should axis deviation or atrial enlargement be categorised as abnormal in young athletes? The athlete's electrocardiogram: time for re-appraisal of markers of pathology.
The 2010 European Society of Cardiology (ESC) guidelines for electrocardiogram (ECG) interpretation in athletes are associated with a relatively high false positive rate and warrant modification to improve the specificity without compromising sensitivity. The aim of this study was to investigate whether non-specific anomalies such as axis deviation and atrial enlargement in isolation require further assessment in highly trained young athletes. Between 2003 and 2011, 2533 athletes aged 14-35 years were investigated with 12-lead ECG and echocardiography. Electrocardiograms were analysed for non-training-related (Group 2) changes according to the 2010 ESC guidelines. Results were compared with 9997 asymptomatic controls. Of the 2533 athletes, 329 (13%) showed Group 2 ECG changes. Isolated axis deviation and isolated atrial enlargement comprised 42.6% of all Group 2 changes. Athletes revealed a slightly higher prevalence of these anomalies compared with controls (5.5 vs. 4.4%; P = 0.023). Echocardiographic evaluation of athletes and controls with isolated axis deviation or atrial enlargement (n = 579) failed to identify any major structural or functional abnormalities. Exclusion of axis deviation or atrial enlargement reduced the false positive rate from 13 to 7.5% and improved specificity from 90 to 94% with a minimal reduction in sensitivity (91-89.5%). Isolated axis deviation and atrial enlargement comprise a high burden of Group 2 changes in athletes and do not predict underlying structural cardiac disease. Exclusion of these anomalies from current ESC guidelines would improve specificity and cost-effectiveness of pre-participation screening with ECG.


Palliative care and the aggressiveness of end-of-life care in patients with advanced pancreatic cancer.
We examined the impact of palliative care (PC) on aggressiveness of end-of-life care for patients with advanced pancreatic cancer. Measures of aggressive care included chemotherapy within 14 days of death; and at least one intensive care unit (ICU) admission, more than one emergency department (ED) visit, and more than one hospitalization, all within 30 days of death. A retrospective population-based cohort study using administrative data was conducted in patients with advanced pancreatic cancer from 2005 to 2010 in Ontario, Canada. Multivariable logistic regression was performed with the above measures of aggressive care as the outcomes of interest and PC as the main exposure, adjusting for covariables. Secondary analyses examined intensity of PC as the main exposure defined in two ways: 1) absolute number of PC visits before the outcome of interest (0, 1, 2, 3+ visits) and 2) monthly rate of PC visits. The cohort included 5381 patients (median survival 75 days); 2816 (52.3%) had received a PC consultation. PC consultation was associated with decreased use of chemotherapy near death (odds ratio [OR] = 0.34, 95% confidence interval [CI] = 0.25 to 0.46); lower risk of ICU admission: OR = 0.12, 95% CI = 0.08 to 0.18; multiple ED visits: OR = 0.19, 95% CI = 0.16 to 0.23; multiple hospitalizations near death: OR = 0.24, 95% CI = 0.19 to 0.31). A per-unit increase in the monthly rate of PC visits was associated with lower odds of aggressive care for all four outcomes. PC consultation and a higher intensity of PC were associated with less aggressive care near death in patients with advanced pancreatic cancer.


A pragmatic randomised controlled trial of the effectiveness and cost-effectiveness of screening older women for the prevention of fractures: rationale, design and methods for the SCOOP study.
SCOOP is a UK seven-centre, pragmatic, randomised controlled trial with 5-year follow-up, including 11,580 women aged 70 to 85 years, to assess the effectiveness and cost-effectiveness of a community-based screening programme to reduce fractures. It utilises the FRAX algorithm and DXA to assess the 10-year probability of fracture. Introduction Osteoporotic, or low-trauma, fractures present a considerable burden to the National Health Service and have major adverse effects on quality of life, disability and mortality for the individual. Methods Given the availability of efficacious treatments and a risk assessment tool based upon clinical risk factors and bone mineral density, a case exists to undertake a community-based controlled evaluation of screening for subjects at high risk of fracture, under the hypothesis that such a screening programme would reduce fractures in this population. Results This study is a UK seven-centre, unblinded, pragmatic, randomised controlled trial with a 5-year follow-up period. A total of 11,580 women, aged 70 to 85 years and not on prescribed bone protective therapy will be consented to the trial by post via primary care providing 90% power to detect an 18% decrease in fractures. Conclusions Participants will be randomised to either a screening arm or control. Those undergoing screening will have a 10-year fracture probability computed from baseline risk factors together with bone mineral density measured by DXA in selected subjects. Individuals above an age-dependent threshold of fracture probability will be recommended for treatment for the duration of the trial. Subjects in the control arm will receive 'usual care'. Participants will be followed up 6 months after randomisation and annually by postal questionnaires with independent checking of hospital and primary care records. The primary outcome will be the proportion of individuals sustaining fractures in each group. An economic analysis will be carried out to assess cost-effectiveness of screening. A qualitative evaluation will be conducted to examine the acceptability of the process to participants.


Drug use prior to incarceration and associated socio-behavioural factors among males in a provincial correctional facility in Ontario, Canada.
To describe the prevalence of drug use in males in a provincial detention centre during the year before incarceration and to examine the association between socio-demographic and behavioural factors and drug use. In 2009, 500 adult males completed a survey after admission to a provincial detention centre in Ontario. Past-year prevalence rates were calculated for the use of opioids, cocaine, crack and methamphetamine, and by route of administration. Bivariate logistic regression was used to examine associations between drug use and socio-demographic and behavioural factors. More than 56% of participants reported use of opioids, cocaine, crack or methamphetamine in the previous year. Risk factors for blood-borne and sexually transmitted infections were commonly reported for the previous year: 12.2% had injected drugs, 78.0% had had unprotected sex, and 48.0% had had more than one sexual partner. In unadjusted analyses, participants who were older than 24 years were more likely to have used any drugs and to have injected drugs in the previous year. This study provides the first Canadian data in the past decade on drug use by recently incarcerated adults. We found that drug use and behaviours that increase the risk of transmission of sexually transmitted and blood-borne infections remain very common in this population. Incarceration provides an opportunity to provide services and links to programs for people who use drugs, which could decrease drug-related harms to individuals and society.


The shape and tempo of language evolution.
There are approximately 7000 languages spoken in the world today. This diversity reflects the legacy of thousands of years of cultural evolution. How far back we can trace this history depends largely on the rate at which the different components of language evolve. Rates of lexical evolution are widely thought to impose an upper limit of 6000-10,000 years on reliably identifying language relationships. In contrast, it has been argued that certain structural elements of language are much more stable. Just as biologists use highly conserved genes to uncover the deepest branches in the tree of life, highly stable linguistic features hold the promise of identifying deep relationships between the world's languages. Here, we present the first global network of languages based on this typological information. We evaluate the relative evolutionary rates of both typological and lexical features in the Austronesian and Indo-European language families. The first indications are that typological features evolve at similar rates to basic vocabulary but their evolution is substantially less tree-like. Our results suggest that, while rates of vocabulary change are correlated between the two language families, the rates of evolution of typological features and structural subtypes show no consistent relationship across families.


Examining the effectiveness of general practitioner and nurse promotion of electronic cigarettes versus standard care for smoking reduction and abstinence in hardcore smokers with smoking-related chronic disease: protocol for a randomised controlled trial.
Despite the clear harm associated with smoking tobacco, many people with smoking-related chronic diseases or serious mental illnesses (SMI) are unwilling or unable to stop smoking. In many cases, these smokers have tried and exhausted all methods to stop smoking and yet clinicians are repeatedly mandated to offer them during routine consultations. Providing nicotine through electronic cigarettes (e-cigarettes) may reduce the adverse health consequences associated with tobacco smoking, but these are not currently offered. The aim of this study is to examine the feasibility, acceptability and effectiveness of general practitioners (GPs) and nurses delivering a brief advice intervention on e-cigarettes and offering an e-cigarette starter pack and patient support resources compared with standard care in smokers with smoking-related chronic diseases or SMI who are unwilling to stop smoking. This is an individually randomised, blinded, two-arm trial. Smokers with a smoking-related chronic condition or SMI with no intention of stopping smoking will be recruited through primary care registers. Eligible participants will be randomised to one of two groups if they decline standard care for stopping smoking: a control group who will receive no additional support beyond standard care; or an intervention group who will receive GP or nurse-led brief advice about e-cigarettes, an e-cigarette starter pack with accompanying practical support booklet, and telephone support from experienced vapers and online video tutorials. The primary outcome measures will be smoking reduction, measured through changes in cigarettes per day and 7-day point-prevalence abstinence at 2 months. Secondary outcomes include smoking reduction, 7-day point-prevalence abstinence and prolonged abstinence at 8 months. Other outcomes include patient recruitment and follow-up, patient uptake and use of e-cigarettes, nicotine intake, contamination of randomisation and practitioner adherence to the delivery of the intervention. Qualitative interviews will be conducted in a subsample of practitioners, patients and the vape team to garner their reactions to the programme. This is the first randomised controlled trial to investigate whether e-cigarette provision alongside a brief intervention delivered by practitioners leads to reduced smoking and abstinence among smokers with smoking-related chronic diseases or SMI. ISRCTN registry, ISRCTN59404712. Registered 28/11/17.


Curcumin suppresses crosstalk between colon cancer stem cells and stromal fibroblasts in the tumor microenvironment: potential role of EMT.
Interaction of stromal and tumor cells plays a dynamic role in initiating and enhancing carcinogenesis. In this study, we investigated the crosstalk between colorectal cancer (CRC) cells with stromal fibroblasts and the anti-cancer effects of curcumin and 5-Fluorouracil (5-FU), especially on cancer stem cell (CSC) survival in a 3D-co-culture model that mimics in vivo tumor microenvironment. Colon carcinoma cells HCT116 and MRC-5 fibroblasts were co-cultured in a monolayer or high density tumor microenvironment model in vitro with/without curcumin and/or 5-FU. Monolayer tumor microenvironment co-cultures supported intensive crosstalk between cancer cells and fibroblasts and enhanced up-regulation of metastatic active adhesion molecules (β1-integrin, ICAM-1), transforming growth factor-β signaling molecules (TGF-β3, p-Smad2), proliferation associated proteins (cyclin D1, Ki-67) and epithelial-to-mesenchymal transition (EMT) factor (vimentin) in HCT116 compared with tumor mono-cultures. High density tumor microenvironment co-cultures synergistically increased tumor-promoting factors (NF-κB, MMP-13), TGF-β3, favored CSC survival (characterized by up-regulation of CD133, CD44, ALDH1) and EMT-factors (increased vimentin and Slug, decreased E-cadherin) in HCT116 compared with high density HCT116 mono-cultures. Interestingly, this synergistic crosstalk was even more pronounced in the presence of 5-FU, but dramatically decreased in the presence of curcumin, inducing biochemical changes to mesenchymal-epithelial transition (MET), thereby sensitizing CSCs to 5-FU treatment. Enrichment of CSCs, remarkable activation of tumor-promoting factors and EMT in high density co-culture highlights that the crosstalk in the tumor microenvironment plays an essential role in tumor development and progression, and this interaction appears to be mediated at least in part by TGF-β and EMT. Modulation of this synergistic crosstalk by curcumin might be a potential therapy for CRC and suppress metastasis.


Ancient mtDNA analysis of early 16(th) century Caribbean cattle provides insight into founding populations of New World creole cattle breeds.
The Columbian Exchange resulted in a widespread movement of humans, plants and animals between the Old and New Worlds. The late 15(th) to early 16(th) century transfer of cattle from the Iberian Peninsula and Canary Islands to the Caribbean laid the foundation for the development of American creole cattle (Bos taurus) breeds. Genetic analyses of modern cattle from the Americas reveal a mixed ancestry of European, African and Indian origins. Recent debate in the genetic literature centers on the 'African' haplogroup T1 and its subhaplogroups, alternatively tying their origins to the initial Spanish herds, and/or from subsequent movements of taurine cattle through the African slave trade. We examine this problem through ancient DNA analysis of early 16(th) century cattle bone from Sevilla la Nueva, the first Spanish colony in Jamaica. In spite of poor DNA preservation, both T3 and T1 haplogroups were identified in the cattle remains, confirming the presence of T1 in the earliest Spanish herds. The absence, however, of "African-derived American" haplotypes (AA/T1c1a1) in the Sevilla la Nueva sample, leaves open the origins of this sub-haplogroup in contemporary Caribbean cattle.


Kidney disease profile and encountered problems during follow-up in Syrian refugee children: a multicenter retrospective study.
Children are one of the most vulnerable groups in conflict zones, especially those with chronic diseases. This study aimed to investigate kidney disease profiles and problems during follow-up in a population of Syrian refugee children residing in Turkey. Syrian refugee children aged between 0 and 18 years were included in the study. Demographic data, diagnosis, particular interventions due to nephrological problems, and problems encountered during follow-up were obtained from all participating pediatric nephrology centers. Data from 633 children from 22 pediatric nephrology centers were included. Mean age of the children was 94.8 ± 61.7 months and 375 were male (59%). 57.7% had parental consanguinity and 23.3% had a close relative(s) with kidney disease. The most common kidney diseases were congenital anomalies of the kidney and urinary tract (CAKUT) (31.0%), glomerular disease (19.9%), chronic kidney disease (CKD) (14.8%), and urolithiasis (10.7%). Frequent reasons for CAKUT were nonobstructive hydronephrosis (23.0%), vesico-ureteral reflux (18.4%), and neurogenic bladder (15.8%). The most common etiology of glomerular diseases was nephrotic syndrome (69%). Ninety-four children had CKD, and 58 children were on chronic dialysis. Six children had kidney transplantation. Surgical intervention was performed on 111 patients. The language barrier, lack of medical records, and frequent disruptions in periodic follow-ups were the main problems noted. CAKUT, glomerular disease, and CKD were highly prevalent in Syrian refugee children. Knowing the frequency of chronic diseases and the problems encountered in refugees would facilitate better treatment options and preventive measures.


Improved aging properties of bio-bitumen coating sheets by using modified lignin.
Papermaking waste liquid (black liquor) is a serious source of water pollution worldwide. The subsequent treatment of it is very difficult cause it contains a large amount of lignin, inorganic salts, organic matter, and pigments, which lead to serious water pollution. Lignin is the main by-product of the paper industry and is the only natural aromatic recyclable resource. Its effective utilization rate is currently less than 3%. Therefore, how to effectively recycle lignin in papermaking waste liquid and further synthesize industrialized products is of great significance to the sustainable development and environmental protection. Besides, based on the shortage of petroleum resources in recent years, the application of biomass resources instead of petroleum resources in the industry is also an important issue. In this article, we explored the best optimal conditions for the oxypropylation and esterification of lignin, and prepared bio-bitumen based on modified lignin, and then applied it to the waterproof coating sheets. FTIR and mechanical properties (softening point, low-temperature flexibility, peel strength, etc.) were tested on the obtained waterproof coating sheets. The results show that the addition of modified lignin reduced the softening point and peel strength of the coating sheets. Interestingly, both oxypropylated lignin (OL) and esterified lignin (OEL) were very beneficial to resist the decrease in peel strength during the aging process, showing a significant improvement in the performance of the coating sheets after aging compared to the control.


Effects of fetal antiepileptic drug exposure: outcomes at age 4.5 years.
To examine outcomes at age 4.5 years and compare to earlier ages in children with fetal antiepileptic drug (AED) exposure. The NEAD Study is an ongoing prospective observational multicenter study, which enrolled pregnant women with epilepsy on AED monotherapy (1999-2004) to determine if differential long-term neurodevelopmental effects exist across 4 commonly used AEDs (carbamazepine, lamotrigine, phenytoin, or valproate). The primary outcome is IQ at 6 years of age. Planned analyses were conducted using Bayley Scales of Infant Development (BSID at age 2) and Differential Ability Scale (IQ at ages 3 and 4.5). Multivariate intent-to-treat (n = 310) and completer (n = 209) analyses of age 4.5 IQ revealed significant effects for AED group. IQ for children exposed to valproate was lower than each other AED. Adjusted means (95% confidence intervals) were carbamazepine 106 (102-109), lamotrigine 106 (102-109), phenytoin 105 (102-109), valproate 96 (91-100). IQ was negatively associated with valproate dose, but not other AEDs. Maternal IQ correlated with child IQ for children exposed to the other AEDs, but not valproate. Age 4.5 IQ correlated with age 2 BSID and age 3 IQ. Frequency of marked intellectual impairment diminished with age except for valproate (10% with IQ <70 at 4.5 years). Verbal abilities were impaired for all 4 AED groups compared to nonverbal skills. Adverse cognitive effects of fetal valproate exposure persist to 4.5 years and are related to performances at earlier ages. Verbal abilities may be impaired by commonly used AEDs. Additional research is needed.


Effect of age on cervical spine injuries in children after motor vehicle collisions: effectiveness of restraint devices.
Despite the devastating consequences of cervical spine (C-spine) injury in children after motor vehicle collisions (MVC), the factors leading to the injury and the appropriateness of protective restraints remain undefined. The authors hypothesized that age-related anatomic factors contribute to inadequate restraints and therefore increase injury severity after MVC. Data on children (<18 years, 1997 to 2002) admitted to a level 1 pediatric trauma center were prospectively collected and retrospectively reviewed. Those with C-spine injuries caused by MVC were extracted and divided into 2 groups: young (0 to 8 years) and old (9 to 18 years). Statistical comparison was by Student's t test or Z-test, with P less than.05 accepted as significant. Of 5,117 trauma admissions, 94 had C-spine injuries with a mean age of 11 +/- 5 years, 66% of which were boys. Among 1,124 patients who had sustained MVC there were 27 C-spine injuries (2.4% incidence), of which, 12 were less than 8 and 15 were older than 8 years. Restraint devices were utilized at least as frequently in younger children (young, 58% v. old, 43%; not significant). However, younger children had an increased incidence of permanent cord deficit (young, 57% v. old, 13%; P <.05) and closed head injury (young, 50% v. old, 7%; P <.05) even while wearing restraint devices, suggesting that restraint devices are inadequate or improperly used in younger patients. This is supported by the increased injury severity scores of the younger group (young, 37.7 +/- 8.5 v. old, 16.5 +/- 4.6; P <.05). Younger children suffer more sever cervical spine injuries after motor vehicle collisions than their older counterparts, in part because of the inadequacy of currently existing restraint devices. Design modifications to current restraints, including the use of head straps, might improve outcome after MVC in younger patients.


PhenoPhyte: a flexible affordable method to quantify 2D phenotypes from imagery.
Accurate characterization of complex plant phenotypes is critical to assigning biological functions to genes through forward or reverse genetics. It can also be vital in determining the effect of a treatment, genotype, or environmental condition on plant growth or susceptibility to insects or pathogens. Although techniques for characterizing complex phenotypes have been developed, most are not cost effective or are too imprecise or subjective to reliably differentiate subtler differences in complex traits like growth, color change, or disease resistance. We designed an inexpensive imaging protocol that facilitates automatic quantification of two-dimensional visual phenotypes using computer vision and image processing algorithms applied to standard digital images. The protocol allows for non-destructive imaging of plants in the laboratory and field and can be used in suboptimal imaging conditions due to automated color and scale normalization. We designed the web-based tool PhenoPhyte for processing images adhering to this protocol and demonstrate its ability to measure a variety of two-dimensional traits (such as growth, leaf area, and herbivory) using images from several species (Arabidopsis thaliana and Brassica rapa). We then provide a more complicated example for measuring disease resistance of Zea mays to Southern Leaf Blight. PhenoPhyte is a new cost-effective web-application for semi-automated quantification of two-dimensional traits from digital imagery using an easy imaging protocol. This tool's usefulness is demonstrated for a variety of traits in multiple species. We show that digital phenotyping can reduce human subjectivity in trait quantification, thereby increasing accuracy and improving precision, which are crucial for differentiating and quantifying subtle phenotypic variation and understanding gene function and/or treatment effects.


Hydration structure and water exchange kinetics at xenotime-water interfaces: implications for rare earth minerals separation.
Hydration of surface ions gives rise to structural heterogeneity and variable exchange kinetics of water at complex mineral-water interfaces. Here, we employ ab initio molecular dynamics (AIMD) simulations and water adsorption calorimetry to examine the aqueous interfaces of xenotime, a phosphate mineral that contains predominantly Y3+ and heavy rare earth elements. Consistent with natural crystal morphology, xenotime is predicted to have a tetragonal prismatic shape, dominated by the {100} surface. Hydration of this surface induces multilayer interfacial water structures with distinct OH orientations, which agrees with recent crystal truncation rod measurements. The exchange kinetics between two adjacent water layers exhibits a wide range of underlying timescales (5-180 picoseconds), dictated by ion-water electrostatics. Adsorption of a bidentate hydroxamate ligand reveals that {100} xenotime surface can only accommodate monodentate coordination with water exchange kinetics strongly depending on specific ligand orientation, prompting us to reconsider traditional strategies for selective separation of rare-earth minerals.


Defining the role of omics in assessing ecosystem health: Perspectives from the Canadian environmental monitoring program.
Scientific reviews and studies continue to describe omics technologies as the next generation of tools for environmental monitoring, while cautioning that there are limitations and obstacles to overcome. However, omics has not yet transitioned into national environmental monitoring programs designed to assess ecosystem health. Using the example of the Canadian Environmental Effects Monitoring (EEM) program, the authors describe the steps that would be required for omics technologies to be included in such an established program. These steps include baseline collection of omics endpoints across different species and sites to generate a range of what is biologically normal within a particular ecosystem. Natural individual variability in the omes is not adequately characterized and is often not measured in the field, but is a key component to an environmental monitoring program, to determine the critical effect size or action threshold for management. Omics endpoints must develop a level of standardization, consistency, and rigor that will allow interpretation of the relevance of changes across broader scales. To date, population-level consequences of routinely measured endpoints such as reduced gonad size or intersex in fish is not entirely clear, and the significance of genome-wide molecular, proteome, or metabolic changes on organism or population health is further removed from the levels of ecological change traditionally managed. The present review is not intended to dismiss the idea that omics will play a future role in large-scale environmental monitoring studies, but rather outlines the necessary actions for its inclusion in regulatory monitoring programs focused on assessing ecosystem health.


Common Visual Preference for Curved Contours in Humans and Great Apes.
Among the visual preferences that guide many everyday activities and decisions, from consumer choices to social judgment, preference for curved over sharp-angled contours is commonly thought to have played an adaptive role throughout human evolution, favoring the avoidance of potentially harmful objects. However, because nonhuman primates also exhibit preferences for certain visual qualities, it is conceivable that humans' preference for curved contours is grounded on perceptual and cognitive mechanisms shared with extant nonhuman primate species. Here we aimed to determine whether nonhuman great apes and humans share a visual preference for curved over sharp-angled contours using a 2-alternative forced choice experimental paradigm under comparable conditions. Our results revealed that the human group and the great ape group indeed share a common preference for curved over sharp-angled contours, but that they differ in the manner and magnitude with which this preference is expressed behaviorally. These results suggest that humans' visual preference for curved objects evolved from earlier primate species' visual preferences, and that during this process it became stronger, but also more susceptible to the influence of higher cognitive processes and preference for other visual features.


Validity and reliability of a quantitative food frequency questionnaire measuring n-3 fatty acid intakes in cardiac patients in the Midwest: a validation pilot study.
The purpose of this pilot study was to test the validity and reliability of a quantitative n-3 fatty acid food frequency questionnaire (FFQ) for later use with larger groups of individuals. A convenience sample of heart patients provided dietary data via three 24-hour food recalls and FFQs. Participants were women (n=17) and men (n=11), 43 to 77 years of age. The association of mean daily intake of n-3 fatty acids obtained using food recalls and the FFQ was assessed by Pearson correlation. The reliability of the FFQ was assessed using coefficient alpha. Correlation of n-3 fatty acid intake using the food recalls and the FFQ was r=0.42 (P<0.05). The coefficient alpha for the test-retest of the FFQ was .83. The top two foods, walnuts and flaxseed, contributed 58% of the n-3 fatty acid intake, and the third food, salmon, contributed 5%. This quantitative n-3 FFQ is a valid instrument for use in place of food recalls for estimating n-3 fatty acid intakes in heart patients and is a reliable instrument to estimate n-3 fatty acid intakes from plant, animal, and seafood sources. The FFQ should be tested in a larger population. Registered dietitians can use this FFQ to screen for intakes, educate patients on food sources, and measure change in intakes after nutrition intervention.


Predicting dentists' decisions: a choice-based conjoint analysis of Medicaid participation.
Private practice dentists are the major source of care for the dental safety net; however, the proportion of dentists who participate in state Medicaid programs is low, often due to poor perceptions of the program's administration and patient population. Using a discrete choice experiment and a series of hypothetical scenarios, this study evaluated trade-offs dentists make when deciding to accept Medicaid patients. An online choice-based conjoint survey was sent to 272 general dentists in Iowa. Hypothetical scenarios presented factors at systematically varied levels. The primary determination was whether dentists would accept a new Medicaid patient in each scenario. Using an ecological model of behavior, determining factors were selected from the categories of policy, administration, community, and patient population to estimate dentists' relative preferences. 62 percent of general dentists responded to the survey. The probability of accepting a new Medicaid patient was highest (81 percent) when reimbursement rates were 85 percent of the dentist's fees, patients never missed appointments, claims were approved on first submission, and no other practices in the area accepted Medicaid. Although dentists preferred higher reimbursement rates, 56 percent would still accept a new Medicaid patient when reimbursement decreased to 55 percent if they were told that the patient would never miss appointments and claims would be approved on initial submission. This study revealed trade-offs that dentists make when deciding to participate in Medicaid. Findings indicate that states can potentially improve Medicaid participation without changing reimbursement rates by making improvements in claims processing and care coordination to reduce missed appointments.


Theoretical and Empirical Analysis of a Spatial EA Parallel Boosting Algorithm.
Many real-world problems involve massive amounts of data. Under these circumstances learning algorithms often become prohibitively expensive, making scalability a pressing issue to be addressed. A common approach is to perform sampling to reduce the size of the dataset and enable efficient learning. Alternatively, one customizes learning algorithms to achieve scalability. In either case, the key challenge is to obtain algorithmic efficiency without compromising the quality of the results. In this article we discuss a meta-learning algorithm (PSBML) that combines concepts from spatially structured evolutionary algorithms (SSEAs) with concepts from ensemble and boosting methodologies to achieve the desired scalability property. We present both theoretical and empirical analyses which show that PSBML preserves a critical property of boosting, specifically, convergence to a distribution centered around the margin. We then present additional empirical analyses showing that this meta-level algorithm provides a general and effective framework that can be used in combination with a variety of learning classifiers. We perform extensive experiments to investigate the trade-off achieved between scalability and accuracy, and robustness to noise, on both synthetic and real-world data. These empirical results corroborate our theoretical analysis, and demonstrate the potential of PSBML in achieving scalability without sacrificing accuracy.


[Modafinil in psychiatric disorders: the promising state reconsidered].
For more than two decades psychiatrists have known about and have promoted modafinil, a very promising stimulant that boosts wakefulness in cases of narcolepsy and also enhances cognitive functions. At present, however, we must conclude that modafinil is hardly ever used to treat illness other than narcolepsy. To review current attitudes and practice with regard to the use and efficacy of modafinil in the treatment of psychiatric disorders. Relevant placebo-controlled studies were retrieved via PubMed (Medline) and Web of Science. Modafinil is used experimentally to treat ADHD, mood disorders, schizophrenia and substance-dependence. Compared to placebo, modafinil achieves positive but mainly variable results on different clinical and cognitive measures. It achieves results very rapidly, within a week, but over a period of time the results stabilise. Modafinil is particularly successful in the treatment of ADHD, depression and cocaine-dependency on measures of attention and hyperactivity, fatigue and cocaine-use respectively. There is a need for further placebo-controlled trials with longer follow-up periods and larger sample size in order to ensure the safety of the product and to refine its area of efficacy.


The challenges of glycan recognition with natural and artificial receptors.
Glycans - simple or complex carbohydrates - play key roles as recognition determinants and modulators of numerous physiological and pathological processes. Thus, many biotechnological, diagnostic and therapeutic opportunities abound for molecular recognition entities that can bind glycans with high selectivity and affinity. This review begins with an overview of the current biologically and synthetically derived glycan-binding scaffolds that include antibodies, lectins, aptamers and boronic acid-based entities. It is followed by a more detailed discussion on various aspects of their generation, structure and recognition properties. It serves as the basis for highlighting recent key developments and technical challenges that must be overcome in order to fully deal with the specific recognition of a highly diverse and complex range of glycan structures.


Detection of rhinovirus in induced sputum at exacerbation of chronic obstructive pulmonary disease.
Common colds are associated with exacerbations of chronic obstructive pulmonary disease (COPD). However, the role of the common cold virus (human rhinovirus) in the production of symptoms and lower airway inflammation at COPD exacerbation is unknown. Thirty three patients with moderate-to-severe COPD were seen at baseline, when the number of chest infections in the previous year was noted, and acutely at COPD exacerbation. Within 48 h after the onset of the exacerbation and at baseline, nasal aspirates and induced sputum were taken for rhinovirus reverse transcriptase polymerase chain reaction (RT-PCR) analysis and determination of cytokine levels. Symptoms, recorded on diary cards, were noted and forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) measured. At exacerbation, mean FEV1 and FVC fell significantly from baseline (p<0.001). Ten of 43 exacerbations were associated with rhinovirus infection, detected in induced sputum. In four of these, nasopharyngeal samples contained no detectable rhinovirus. All baseline samples were negative for rhinovirus. The simultaneous presence of increased nasal discharge/nasal congestion (in 26 of the 43 exacerbations) and increased sputum (29 exacerbations) was strongly associated with the presence of rhinovirus (odds ratio 6.15; p=0.036). Total symptom scores were greater for rhinovirus as compared to nonrhinovirus exacerbations (p=0.039). Median baseline sputum interleukin-6 levels rose from 90.2 to 140.3 pg x mL(-1) at exacerbation (p=0.005); the change was greater in the presence of rhinovirus infection (p=0.008). Rhinovirus infection can be detected at chronic obstructive pulmonary disease exacerbation. This is associated with elevation of lower airway interleukin-6 levels, which may mediate lower airway symptom expression during chronic obstructive pulmonary disease exacerbations.


The Effects of Preoperative Radiotherapy on Head and Neck Free Flap Anastomosis Success.
The long-term survival benefit of neoadjuvant radiotherapy for oropharyngeal tumors is controversially discussed in the literature. To bring more light into this important debate, we evaluated our cases. In this retrospective study the main focus was the relationship between neoadjuvant irradiation and anastomosis failure. Other influencing factors including previous operative treatment and tumor stage and type also were studied. In total, 7 anastomoses failed (total failure rate, 8.4%; n = 83); 1 of the 7 underwent neoadjuvant irradiation (failure rate, 3.1%; n = 32). All 7 anastomosis failures were in squamous cell carcinoma cases, with 5 of them staged as T4. Our data suggest that neoadjuvant radiotherapy for oropharyngeal carcinoma does not increase the risk of postoperative anastomosis failure compared with surgical reconstruction alone. Furthermore, the data suggest a correlation between the stage and type of tumor.


Diabetes in Asia and the Pacific: Implications for the Global Epidemic.
The last three decades have witnessed an epidemic rise in the number of people with diabetes, especially type 2 diabetes, and particularly in developing countries, where more than 80% of the people with diabetes live. The rise of type 2 diabetes in South Asia is estimated to be more than 150% between 2000 and 2035. Although aging, urbanization, and associated lifestyle changes are the major determinants for the rapid increase, an adverse intrauterine environment and the resulting epigenetic changes could also contribute in many developing countries. The International Diabetes Federation estimated that there were 382 million people with diabetes in 2013, a number surpassing its earlier predictions. More than 60% of the people with diabetes live in Asia, with almost one-half in China and India combined. The Western Pacific, the world's most populous region, has more than 138.2 million people with diabetes, and the number may rise to 201.8 million by 2035. The scenario poses huge social and economic problems to most nations in the region and could impede national and, indeed, global development. More action is required to understand the drivers of the epidemic to provide a rationale for prevention strategies to address the rising global public health "tsunami." Unless drastic steps are taken through national prevention programs to curb the escalating trends in all of the countries, the social, economic, and health care challenges are likely to be insurmountable.


Cross-protective immunity to influenza A viruses.
Antigenic changes in influenza virus occur gradually, owing to mutations (antigenic drift), and abruptly, owing to reassortment among subtypes (antigenic shift). Availability of strain-matched vaccines often lags behind these changes, resulting in a shortfall in public health. In animal models, cross-protection by vaccines based on conserved antigens does not completely prevent infection, but greatly reduces morbidity, mortality, virus replication and, thus, viral shedding and spread. Such immunity is especially effective and long-lasting with mucosal administration. Cross-protective immunity in humans is controversial, but is suggested by some epidemiological findings. 'Universal' vaccines protective against all influenza A viruses might substantially reduce severity of infection and limit spread of disease during outbreaks. These vaccines could be used 'off the shelf' early in an outbreak or pandemic, before strain-matched vaccines are available.


Association of suboptimal health status with psychosocial stress, plasma cortisol and mRNA expression of glucocorticoid receptor α/β in lymphocyte.
Suboptimal health status (SHS) has become a new public health challenge in China. This study investigated whether high SHS is associated with psychosocial stress, changes in cortisol level and/or glucocorticoid receptor (GR) isoform expression. Three-hundred eighty-six workers employed in three companies in Beijing were recruited. The SHS score was derived from data collection in the SHS questionnaire (SHSQ-25). The short standard version of the Copenhagen Psychosocial Questionnaire (COPSOQ) was used to assess job-related psychosocial stress. The mean value of the five scales of COPSOQ and distribution of plasma cortisol and mRNA expression of GRα/GRβ between the high level of SHS group and the low level of SHS group were compared using a general linear model procedure. Multiple linear regression analysis was used to analyze the effect of psychosocial stress on SHS. We identified three factors that were predictive of SHS, including "demands at work", "interpersonal relations and leadership" and "insecurity at work". Significantly higher levels of plasma cortisol and GRβ/GRα mRNA ratio were observed among the high SHS group. High level of SHS is associated with decreased mRNA expression of GRα. This study confirmed the association between chronic psychosocial stress and SHS, indicating that improving the psychosocial work environment may reduce SHS and then prevent chronic diseases effectively.


Curcumin treatment enhances the repair and regeneration of wounds in mice exposed to hemibody gamma-irradiation.
Hemibody irradiation in multiple fractionated doses is frequently used for the treatment of various neoplastic disorders. It produces both acute and late effects on the skin and subcutaneous tissues that have profound implications in the healing of surgical wounds. Because of the crucial practical importance of hemibody radiation exposure associated with skin wounds, it is imperative to investigate the efficacy of cost-effective herbal products in the reconstruction of irradiated wounds. Therefore, the effect of pretreatment of curcumin was studied on the healing of excision wound in mice exposed to 2, 4, 6, or 8 Gy of hemibody gamma-radiation. A full-thickness skin wound was created by removing the skin flap of the dorsum of 8- to 10-week-old Swiss albino mice partially (lower half, below the rib cage) exposed to 2, 4, 6, or 8 Gy of gamma-radiation. The progression of wound contraction was monitored periodically by capturing video images of the wound, where the first image of each wound from different groups was obtained 1 day after wounding and that day was considered as day 0. Eight animals were used in each group at each exposure dose for wound contraction studies. Furthermore, the effect of curcumin on mean healing time after exposure of mice to 2, 4, 6, or 8Gy of hemibody gamma-radiation was also evaluated, where eight animals were used in each group at each exposure dose. Collagen, hexosamine, DNA, nitric oxide, and histologic profiles were also evaluated during the course of healing of excision wounds at days 4, 8, and 12 after irradiation treated or not with curcumin before exposure to 0 or 6 Gy of gamma-radiation. Six animals were used in each group at each interval for each biochemical parameter studied, except for histologic evaluations, where four animals were used in each group at each interval. Exposure of mice to different doses of gamma-radiation resulted in a dose-dependent delay in contraction and wound-healing time of excision wound, whereas curcumin pretreatment caused a significant elevation in the rate of wound contraction and a decrease in the mean wound-healing time. Treatment with curcumin before irradiation enhanced the synthesis of collagen, hexosamine, DNA, nitrite, and nitrate, and histologic assessment of wound biopsy specimens revealed improved collagen deposition and an increase in fibroblast and vascular densities. The authors' study demonstrates that curcumin pretreatment has a conducive effect on the irradiated wound and could be a substantial therapeutic strategy for ameliorating radiation-induced delay in wound repair in cases of radiation-induced skin injuries.


It is all me: the effect of viewpoint on visual-vestibular recalibration.
Participants performed a visual-vestibular motor recalibration task in virtual reality. The task consisted of keeping the extended arm and hand stable in space during a whole-body rotation induced by a robotic wheelchair. Performance was first quantified in a pre-test in which no visual feedback was available during the rotation. During the subsequent adaptation phase, optical flow resulting from body rotation was provided. This visual feedback was manipulated to create the illusion of a smaller rotational movement than actually occurred, hereby altering the visual-vestibular mapping. The effects of the adaptation phase on hand stabilization performance were measured during a post-test that was identical to the pre-test. Three different groups of subjects were exposed to different perspectives on the visual scene, i.e., first-person, top view, or mirror view. Sensorimotor adaptation occurred for all three viewpoint conditions, performance in the post-test session showing a marked under-compensation relative to the pre-test performance. In other words, all viewpoints gave rise to a remapping between vestibular input and the motor output required to stabilize the arm. Furthermore, the first-person and mirror view adaptation induced a significant decrease in variability of the stabilization performance. Such variability reduction was not observed for the top view adaptation. These results suggest that even if all three viewpoints can evoke substantial adaptation aftereffects, the more naturalistic first-person view and the richer mirror view should be preferred when reducing motor variability constitutes an important issue.


Production and characterization of mouse monoclonal antibodies against human monocyte chemoattractant protein-1.
We developed five different hybridoma cell lines that produced mAb against human monocyte chemoattractant protein-1 (MCP-1). The subclass of all five antibodies was IgG1. All five mAb formed complexes with metabolically labeled MCP-1 that could be demonstrated by immunoprecipitation. The antibodies were specific for MCP-1. They did not cross-react by immunoprecipitation with structurally related host defense cytokines present in metabolically labeled PHA- or LPS-stimulated mononuclear cell culture fluids, nor did they cross-react in a direct ELISA with neutrophil attractant/activation protein-1, with crude platelet lysate proteins, or with pure platelet proteins that have amino acids sequences similar to that of MCP-1. The mAb also reacted with rMCP-1 expressed in Escherichia coli, suggesting that they recognize protein structure rather than the glycosylated portion of human MCP-1. When the mAb were mixed with MCP-1, the monocyte chemotactic response to MCP-1 was inhibited. A sandwich ELISA was developed to detect MCP-1 in biologic fluids containing relatively high concentrations of other proteins. The sensitivity was 300 pg/ml, or 30 pg/ELISA well. An anti-MCP-1 mAb column was used in an improved method of MCP-1 purification. Approximately 240 micrograms of MCP-1 were purified from 5 liters of FCS-containing U-105MG cell culture supernatant. The yield was at least 60%. In addition to two forms of MCP-1 reported previously by us, two more forms of MCP-1 were found in a mixture of culture supernatants of PHA- and LPS-stimulated human PBMC.


Preventing gut leakiness by oats supplementation ameliorates alcohol-induced liver damage in rats.
Only 30% of alcoholics develop liver disease (ALD) suggesting that additional factors are needed. Endotoxin is one such factor, but its etiology is unclear. Since the gut is the main source of endotoxin, we sought to determine whether an increase in intestinal permeability (leaky gut) is required for alcohol-induced endotoxemia and liver injury and whether the gut leakiness is preventable. For 10 weeks, rats received by gavage increasing alcohol doses (to 8 g/kg/day) and either oats (10 g/kg) or chow b.i.d. Intestinal permeability was then assessed by urinary excretion of lactulose and mannitol. Liver injury was evaluated histologically, biochemically (liver fat content), and by serum aminotransferase. Alcohol caused gut leakiness that was associated with both endotoxemia and liver injury. Oats prevented these changes. We conclude that chronic gavage of alcohol in rats is a simple experimental model that mimics key aspects of ALD, including endotoxemia and liver injury, and can be useful to study possible mechanisms of endotoxemia in ALD. Since preventing the gut leakiness by oats also prevented the endotoxemia and ameliorated liver damage in rat, our results suggest that alcohol-induced gut leakiness 1) may cause alcohol-induced endotoxemia and liver injury and 2) may be the critical cofactor in the 30% of alcoholics who develop ALD. Further studies are needed to determine whether ALD in humans can be prevented by preventing alcohol-induced gut leakiness, studies that should lead to the development of useful therapeutic agents for the prevention of ALD.


Genetics Consultation Rates Following a Diagnosis of High-Grade Serous Ovarian Carcinoma in the Canadian Province of Ontario.
In 2001, the province of Ontario expanded cancer genetic testing eligibility to include all women with high-grade serous ovarian carcinoma (HGSC) of the ovary, fallopian tube, and peritoneum. The aim of this study was to determine the proportion of women who attended genetics counseling for consideration of BRCA1/2 gene analysis. We also sought to examine if regional differences in consultation rate exist across administrative health regions in the province of Ontario. We identified all women with a pathological diagnosis of HGSC in the province of Ontario between 1997 until 2011. Our primary outcome was the 2-year rate of genetics consultation following a diagnosis of HGSC. We compared consultation rates over time and geographical regions and applied multiple logistic regression to identify predictors of genetics consultation. Of the 5412 women with a diagnosis of HGSC over the study period, 6.6% were seen for genetics consultation within 2 years of diagnosis. Factors predictive of genetics consultation included history of breast cancer (odds ratio [OR], 3.56; 95% confidence interval [CI], 1.87-6.78), era of diagnosis (2009-2011 vs 1997-2000; OR, 10.59; 95% CI, 5.02-22.33), and younger age at diagnosis (OR, 0.95; 95% CI, 0.94-0.97 for each additional year). No regional differences in consultation rate were seen. Despite an increasing rate across eras, a small proportion of women with HGSC undergo genetics consultation. Efforts are required to increase cancer genetics consultation in patients with HGSC in the province of Ontario.


Association Between Anatomical Characteristics, Knee Laxity, Muscle Strength, and Peak Knee Valgus During Vertical Drop-Jump Landings.
Controlled laboratory study; cross-sectional. To investigate the relationship among anatomical variables, knee laxity, muscle strength, and peak knee valgus angles during a vertical drop-jump landing task. Excessive knee valgus has been associated with anterior cruciate ligament injury in females; however, the influence of anatomical characteristics, knee laxity, and muscle strength on frontal plane knee motion is not completely understood. Norwegian elite female soccer players (n = 279; mean ± SD age, 21 ± 4 years; height, 167 ± 6 cm; body mass, 63 ± 7 kg) were evaluated from 2009 through 2012. The evaluation included 3-D motion analysis of a vertical drop jump, anatomical measures (height, static knee valgus, leg length, and static foot posture), knee laxity, and muscle strength (quadriceps, hamstrings, and hip abductors). Multiple linear regression analyses were used to investigate the relationships among anatomical characteristics, knee laxity, muscle strength, and peak knee valgus angles. Anatomical characteristics explained 11% of the variance in peak knee valgus angles (P<.001), with height and static knee valgus being significant predictors. Greater body height and static knee valgus were associated with greater peak knee valgus angles during a vertical drop-jump landing task. However, these variables only explained 11% of the variance in peak knee valgus.


Delirium detection in older acute medical inpatients: a multicentre prospective comparative diagnostic test accuracy study of the 4AT and the confusion assessment method.
Delirium affects > 15% of hospitalised patients but is grossly underdetected, contributing to poor care. The 4 'A's Test (4AT, www.the4AT.com ) is a short delirium assessment tool designed for routine use without special training. The primary objective was to assess the accuracy of the 4AT for delirium detection. The secondary objective was to compare the 4AT with another commonly used delirium assessment tool, the Confusion Assessment Method (CAM). This was a prospective diagnostic test accuracy study set in emergency departments or acute medical wards involving acute medical patients aged ≥ 70. All those without acutely life-threatening illness or coma were eligible. Patients underwent (1) reference standard delirium assessment based on DSM-IV criteria and (2) were randomised to either the index test (4AT, scores 0-12; prespecified score of > 3 considered positive) or the comparator (CAM; scored positive or negative), in a random order, using computer-generated pseudo-random numbers, stratified by study site, with block allocation. Reference standard and 4AT or CAM assessments were performed by pairs of independent raters blinded to the results of the other assessment. Eight hundred forty-three individuals were randomised: 21 withdrew, 3 lost contact, 32 indeterminate diagnosis, 2 missing outcome, and 785 were included in the analysis. Mean age was 81.4 (SD 6.4) years. 12.1% (95/785) had delirium by reference standard assessment, 14.3% (56/392) by 4AT, and 4.7% (18/384) by CAM. The 4AT had an area under the receiver operating characteristic curve of 0.90 (95% CI 0.84-0.96). The 4AT had a sensitivity of 76% (95% CI 61-87%) and a specificity of 94% (95% CI 92-97%). The CAM had a sensitivity of 40% (95% CI 26-57%) and a specificity of 100% (95% CI 98-100%). The 4AT is a short, pragmatic tool which can help improving detection rates of delirium in routine clinical care. International standard randomised controlled trial number (ISRCTN) 53388093 . Date applied 30/05/2014; date assigned 02/06/2014.


Vasorelaxing Action of the Kynurenine Metabolite, Xanthurenic Acid: The Missing Link in Endotoxin-Induced Hypotension?
The kynurenine pathway of tryptophan metabolism is activated by pro-inflammatory cytokines. L-kynurenine, an upstream metabolite of the pathway, acts as a putative endothelium-derived relaxing factor, and has been hypothesized to play a causative role in the pathophysiology of inflammation-induced hypotension. Here, we show that xanthurenic acid (XA), the transamination product of 3-hydroxykynurenine, is more efficacious than L-kynurenine in causing relaxation of a resistance artery, but fails to relax pre-contracted aortic rings. In the mesenteric artery, XA enhanced activating phosphorylation of endothelial nitric oxide synthase (NOS), and the relaxing action of XA was abrogated by pharmacological inhibition of NOS and endothelial-derived hyperpolarizing factor. Systemic injection of XA reduced blood pressure in mice, and serum levels of XA increased by several fold in response to a pulse with the endotoxin, lipopolysaccharide (LPS). LPS-induced hypotension in mice was prevented by pre-treatment with the kynurenine monooxygenase (KMO) inhibitor, Ro-618048, which lowered serum levels of XA but enhanced serum levels of L-kynurenine. UPF 648, another KMO inhibitor, could also abrogate LPS-induced hypotension. Our data identify XA as a novel vasoactive compound and suggest that formation of XA is a key event in the pathophysiology of inflammation-induced hypotension.