Lactose synthase components in milk: concentrations of alpha-lactalbumin and beta1,4-galactosyltransferase in milk of cows from several breeds at various stages of lactation.
It is believed that milk production is determined by the number and activity of mammary secretory cells. Secretory activity, as assessed by milk volume, depends on secretion of the major osmole in milk, lactose, which is produced by lactose synthase. The amount of either of the two proteins in lactose synthase may regulate milk production. The objective of this study was to determine whether the concentrations in milk of the two components of lactose synthase, alpha-lactalbumin (alpha-LA) and beta1,4-galactosyltransferase (B4GALT), were related to genetic background, stage of lactation, breed or parity of dairy cows. alpha-Lactalbumin and B4GALT concentrations were measured by ELISA and by enzyme assays, respectively, from single milk samples. Two herds with a total of 279 cows were used in the analysis. One herd contained Ayrshire, Brown Swiss, Holstein and Jersey cows; the second herd contained two groups of cows; Holsteins selected for high milk production and Holsteins with 1960s genetics. The alpha-LA concentration in milk was greater in Jerseys and Ayrshires than in Holsteins and Brown Swiss. However, no difference in alpha-LA concentration was observed in milk from high and low genetic merit cows in the Minnesota herd or among different genetic backgrounds in the Illinois herd. beta1,4-Galactosyltransferase concentrations were similar for all groups that were analyzed. alpha-Lactalbumin concentrations were positively correlated with milk protein concentration, milk fat concentration and lactose concentration. beta1,4-Galactosyltransferase concentration in milk exhibited a strong positive correlation with number of days in milk. Although the concentration of B4GALT increased as lactation progressed, the values did not show any correlation with persistency of lactation or late lactation milk production. In conclusion, this survey shows that the two components of lactose synthase are each correlated to protein concentration and individually correlated to the concentration of other milk components and stage of lactation.


Appearance matters: neural correlates of food choice and packaging aesthetics.
Neuro-imaging holds great potential for predicting choice behavior from brain responses. In this study we used both traditional mass-univariate and state-of-the-art multivariate pattern analysis to establish which brain regions respond to preferred packages and to what extent neural activation patterns can predict realistic low-involvement consumer choices. More specifically, this was assessed in the context of package-induced binary food choices. Mass-univariate analyses showed that several regions, among which the bilateral striatum, were more strongly activated in response to preferred food packages. Food choices could be predicted with an accuracy of up to 61.2% by activation patterns in brain regions previously found to be involved in healthy food choices (superior frontal gyrus) and visual processing (middle occipital gyrus). In conclusion, this study shows that mass-univariate analysis can detect small package-induced differences in product preference and that MVPA can successfully predict realistic low-involvement consumer choices from functional MRI data.


Synthesis and structure of the azidogermyliumylidene azide complex [L(N3)Ge:](+)N3- with covalently and ionically bonded azide ligands at germanium(II) [L = bis(N-heterocyclic carbene)].
Starting from the chlorogermyliumylidene chloride salt [L(Cl)Ge:]Cl (1) (L = 1,1'-methylene-3,3'-di-2,6-diisopropyl-phenylimidazole-2,2'-diylidene), the chloride ion can be easily substituted by BPh4 to yield [L(Cl)Ge:]BPh4 (3). Reaction of the latter with NaN3 furnishes [L(N3)Ge:]BPh4 (4). In contrast, the direct reaction of 1 with NaN3 affords exclusively the first azidogermyliumylidene azide salt [L(N3)Ge:]N3 (2). The latter represents the first isolable diazido Ge(II) complex with a covalently bonded azido ligand and a weakly coordinating azide anion as the counterion. All new compounds 2, 3, and 4 were fully characterized, including using X-ray diffraction analysis.


Folic acid for the prevention of neural tube defects. American Academy of Pediatrics. Committee on Genetics.
The American Academy of Pediatrics endorses the US Public Health Service (USPHS) recommendation that all women capable of becoming pregnant consume 400 microgram of folic acid daily to prevent neural tube defects (NTDs). Studies have demonstrated that periconceptional folic acid supplementation can prevent 50% or more of NTDs such as spina bifida and anencephaly. For women who have previously had an NTD-affected pregnancy, the Centers for Disease Control and Prevention (CDC) recommends increasing the intake of folic acid to 4000 microgram per day beginning at least 1 month before conception and continuing through the first trimester. Implementation of these recommendations is essential for the primary prevention of these serious and disabling birth defects. Because fewer than 1 in 3 women consume the amount of folic acid recommended by the USPHS, the Academy notes that the prevention of NTDs depends on an urgent and effective campaign to close this prevention gap.


Regulatory toxicology perspectives on the development of botanical drug products in the United States.
Toxicological studies constitute an essential part of the effort in developing a botanical supplement into a drug product. The US Food and Drug Administration recently published a draft guidance and established a special botanical review team to assist academic and industry sponsors to manage this and other regulatory considerations related to this unique group of drug products. In this article, the current state of regulatory viewpoints on issues related to requirements and recommendations of various types of nonclinical toxicity studies in support of advanced phases clinical trials and filing a New Drug Application of a botanical are discussed. Topics include nonclinical pharmacology/toxicology view of previous human experience and initial clinical trial, regulatory perspectives on acute toxicity studies, chronic toxicity studies, mutagenicity studies, reproductive toxicity studies, and carcinogenicity studies on botanicals. Certain regulatory review-related issues are also presented. It is anticipated that through a proactive 2-way communication between the Agency and the sponsor, toxicological development of botanical drug product can be significantly facilitated.


Dengue and Zika Virus Cross-Reactive Human Monoclonal Antibodies Protect against Spondweni Virus Infection and Pathogenesis in Mice.
Spondweni virus (SPOV) is the flavivirus that is most closely related to Zika virus (ZIKV). Although SPOV causes sporadic human infections in Africa, recently it was found in Culex mosquitoes in Haiti. To investigate the pathogenic spectrum of SPOV, we developed infection models in mice. Although two SPOV strains failed to cause disease in immunocompetent mice, each accumulated in the brain, spleen, eye, testis, and kidney when type I interferon signaling was blocked and unexpectedly caused infection, immune cell infiltration, and swelling in the ankle. In pregnant mice, SPOV replicated in the placenta and fetus but did not cause placental insufficiency or microcephaly. We identified human antibodies from ZIKV or DENV immune subjects that neutralized SPOV infection and protected against lethal challenge. Our experiments describe similarities and differences in clinical syndromes between SPOV and ZIKV and suggest that their serological relatedness has implications for antibody therapeutics and flavivirus vaccine development.


Predicting Early Post-stroke Aphasia Outcome From Initial Aphasia Severity.
Background: The greatest degree of language recovery in post-stroke aphasia takes place within the first weeks. Aphasia severity and lesion measures have been shown to be good predictors of long-term outcomes. However, little is known about their implications in early spontaneous recovery. The present study sought to determine which factors better predict early language outcomes in individuals with post-stroke aphasia. Methods: Twenty individuals with post-stroke aphasia were assessed <72 h (acute) and 10-14 days (subacute) after stroke onset. We developed a composite score (CS) consisting of several linguistic sub-tests: repetition, oral comprehension and naming. Lesion volume, lesion load and diffusion measures [fractional anisotropy (FA) and axial diffusivity (AD)] from both arcuate fasciculi (AF) were also extracted using MRI scans performed at the same time points. A series of regression analyses were performed to predict the CS at the second assessment. Results: Among the diffusion measures, only FA from right AF was found to be a significant predictor of early subacute aphasia outcome. However, when combined in two hierarchical models with FA, age and either lesion load or lesion size, the initial aphasia severity was found to account for most of the variance (R 2 = 0.678), similarly to the complete models (R 2 = 0.703 and R 2 = 0.73, respectively). Conclusions: Initial aphasia severity was the best predictor of early post-stroke aphasia outcome, whereas lesion measures, though highly correlated, show less influence on the prediction model. We suggest that factors predicting early recovery may differ from those involved in long-term recovery.


Acute and Protracted Cell Death in Light-Induced Retinal Degeneration in the Canine Model of Rhodopsin Autosomal Dominant Retinitis Pigmentosa.
To characterize a light damage paradigm and establish structural and immunocytochemical measures of acute and protracted light-induced retinal degeneration in the rhodopsin (RHO) T4R dog model of RHO-autosomal dominant retinitis pigmentosa (ADRP). Retinal light damage was induced in mutant dogs with a 1-minute exposure to various light intensities (0.1-1.0 mW/cm2) delivered with a Ganzfeld stimulator, or by fundus photography. Photoreceptor cell death was assessed by TUNEL assay, and alterations in retinal layers were examined by histology and immunohistochemistry 24 hours and 2 weeks after light exposure. Detailed topographic maps were made to document changes in the outer retinal layers of all four retinal quadrants 2 weeks post exposure. Twenty-four hours post light exposure, the severity of photoreceptor cell death was dose dependent. Immunohistochemical analysis revealed disruption of rod outer segments, focal loss of the RPE integrity, and an increase in expression of endothelin receptor B in Müller cells with the two highest doses of light and fundus photography. Two weeks after light exposure, persistence of photoreceptor death, thinning of the outer nuclear layer, and induction of Müller cell gliosis occurred with the highest doses of light. We have characterized outcome measures of acute and continuing retinal degeneration in the RHO T4R dog following light exposure. These will be used to assess the molecular mechanisms of light-induced damage and rescue strategies in this large animal model of RHO-ADRP.


White matter microstructure on diffusion tensor imaging is associated with conventional magnetic resonance imaging findings and cognitive function in adolescents born preterm.
Diffusion tensor imaging (DTI) was used to evaluate white matter architecture after preterm birth. The goals were (1) to compare white matter microstructure in two cohorts of preterm- and term-born children; and (2) within preterm groups, to determine if sex, gestational age, birthweight, white matter injury score from conventional magnetic resonance imaging (MRI), or IQ was associated with DTI measures. Participants (n=121; 66 females, 55 males) were aged 9 to 16 years. They comprised 58 preterm children (site 1, n=25; and site 2, n=33) born at less than 36 weeks' gestation (mean 29.4 wks; birthweight 1289g) and 63 term children (site 1, n=40; site 2, n=23) born at more than 37 weeks' gestation. DTI was analyzed using tract-based spatial statistics. Diffusion measures were fractional anisotropy, axial, radial, and mean diffusivity. In no region of the white matter skeleton was fractional anisotropy lower in the preterm group at either site. Within the preterm groups, fractional anisotropy was significantly associated with white matter injury score, but not sex, gestational age, or birthweight. At site 1, fractional anisotropy was associated with IQ. DTI contributes to understanding individual differences after preterm birth but may not differentiate a relatively high-functioning group of preterm children from a matched group of term-born children.


Enhanced discrimination of highly clonal ST22-methicillin-resistant Staphylococcus aureus IV isolates achieved by combining spa, dru, and pulsed-field gel electrophoresis typing data.
ST22-methicillin-resistant Staphylococcus aureus type IV (ST22-MRSA-IV) is endemic in Irish hospitals and is designated antibiogram-resistogram type-pulsed-field group (AR-PFG) 06-01. Isolates of this highly clonal strain exhibit limited numbers of pulsed-field gel electrophoresis (PFGE) patterns and spa types. This study investigated whether combining PFGE and spa typing with DNA sequencing of the staphylococcal cassette chromosome mec element (SCCmec)-associated direct repeat unit (dru typing) would improve isolate discrimination. A total of 173 MRSA isolates recovered in one Irish hospital during periods in 2007 and 2008 were investigated using antibiogram-resistogram (AR), PFGE, spa, dru, and SCCmec typing. Isolates representative of each of the 17 pulsed-field group 01 (PFG-01) spa types identified underwent multilocus sequence typing, and all isolates were ST22. Ninety-seven percent of isolates (168 of 173) exhibited AR-PFG 06-01 or closely related AR patterns, and 163 of these isolates harbored SCCmec type IVh. The combination of PFGE, spa, and dru typing methods significantly improved discrimination of the 168 PFG-01 isolates, yielding 65 type combinations with a Simpson's index of diversity (SID) of 96.53, compared to (i) pairwise combinations of spa and dru typing, spa and PFGE typing, and dru and PFGE typing, which yielded 37, 44, and 43 type combinations with SIDs of 90.84, 91.00, and 93.57, respectively, or (ii) individual spa, dru, and PFGE typing methods, which yielded 17, 17, and 21 types with SIDs of 66.9, 77.83, and 81.34, respectively. Analysis of epidemiological information for a subset of PFG-01 isolates validated the relationships inferred using combined PFGE, spa, and dru typing data. This approach significantly enhances discrimination of ST22-MRSA-IV isolates and could be applied to epidemiological investigations of other highly clonal MRSA strains.


The potential to improve water quality in the middle Rio Grande through effective wetland restoration.
The Rio Grande, which forms the United States-Mexico border for much of its course, receives diverse pollutants from both urban and agricultural areas, most notably in the sister cities of El Paso (TX, USA)-Ciudad Juárez (CHI, Mexico). This study aimed to describe regional trends in water quality in waters near the El Paso-Ciudad Juárez metroplex and to examine the potential for water quality improvement through the use of a created wetland. Very few differences in nutrient chemistry were found among drains, canals and the Rio Grande, with the exception of elevated chloride and lower phosphorus levels found in the drains. Overall, chloride concentrations increased with distance downstream, likely due to concentration of salts via evaporation from irrigated agriculture. A wastewater treatment plant (WWTP) contributed substantially to total phosphorus and nitrate levels, which, together with ammonia, tended to exceed state criteria for water quality downstream of the WWTP outflow. The created Rio Bosque wetlands reduced nitrate concentrations in the water, possibly via denitrification enhanced by algae; algae increased in biomass as water flowed through the wetlands. However, the diversion of water for irrigated agriculture, resulting in the absence of water, and thus aquatic plants, in the wetland in the summer has limited the ability of this wetland to improve regional water quality.


GLUT1-mediated glucose uptake plays a crucial role during Plasmodium hepatic infection.
Intracellular pathogens have evolved mechanisms to ensure their survival and development inside their host cells. Here, we show that glucose is a pivotal modulator of hepatic infection by the rodent malaria parasite Plasmodium berghei and that glucose uptake via the GLUT1 transporter is specifically enhanced in P. berghei-infected cells. We further show that ATP levels of cells containing developing parasites are decreased, which is known to enhance membrane GLUT1 activity. In addition, GLUT1 molecules are translocated to the membrane of the hepatic cell, increasing glucose uptake at later stages of infection. Chemical inhibition of GLUT1 activity leads to a decrease in glucose uptake and the consequent impairment of hepatic infection, both in vitro and in vivo. Our results reveal that changes in GLUT1 conformation and cellular localization seem to be part of an adaptive host response to maintain adequate cellular nutrition and energy levels, ensuring host cell survival and supporting P. berghei hepatic development.


Amplification of microsatellite repeat motifs is associated with the evolutionary differentiation and heterochromatinization of sex chromosomes in Sauropsida.
The sex chromosomes in Sauropsida (reptiles and birds) have evolved independently many times. They show astonishing diversity in morphology ranging from cryptic to highly differentiated sex chromosomes with male (XX/XY) and female heterogamety (ZZ/ZW). Comparing such diverse sex chromosome systems thus provides unparalleled opportunities to capture evolution of morphologically differentiated sex chromosomes in action. Here, we describe chromosomal mapping of 18 microsatellite repeat motifs in eight species of Sauropsida. More than two microsatellite repeat motifs were amplified on the sex-specific chromosome, W or Y, in five species (Bassiana duperreyi, Aprasia parapulchella, Notechis scutatus, Chelodina longicollis, and Gallus gallus) of which the sex-specific chromosomes were heteromorphic and heterochromatic. Motifs (AAGG)n and (ATCC)n were amplified on the W chromosome of Pogona vitticeps and the Y chromosome of Emydura macquarii, respectively. By contrast, no motifs were amplified on the W chromosome of Christinus marmoratus, which is not much differentiated from the Z chromosome. Taken together with previously published studies, our results suggest that the amplification of microsatellite repeats is tightly associated with the differentiation and heterochromatinization of sex-specific chromosomes in sauropsids as well as in other taxa. Although some motifs were common between the sex-specific chromosomes of multiple species, no correlation was observed between this commonality and the species phylogeny. Furthermore, comparative analysis of sex chromosome homology and chromosomal distribution of microsatellite repeats between two closely related chelid turtles, C. longicollis and E. macquarii, identified different ancestry and differentiation history. These suggest multiple evolutions of sex chromosomes in the Sauropsida.


Patient-cooperative strategies for robot-aided treadmill training: first experimental results.
Task-oriented repetitive movements can improve motor performance in patients with neurological or orthopaedic lesions. The application of robotics and automation technology can serve to assist, enhance, evaluate, and document neurological and orthopedic rehabilitation. This paper deals with the application of "patient-cooperative" techniques to robot-aided gait rehabilitation of neurological disorders. We define patient-cooperative to mean that, during movement, the technical system takes into account the patient's intention and voluntary efforts rather than imposing any predefined movements or inflexible strategies. It is hypothesized that such cooperative robotic approaches can improve the therapeutic outcome compared to classical rehabilitation strategies. New cooperative strategies are presented that detect the patient's voluntary efforts. First, this enables the patient increased freedom of movement by a certain amount of robot compliance. Second, the robot behavior adapts to the existing voluntary motor abilities. And third, the robotic system displays and improves the patient contribution by visual biofeedback. Initial experimental results are presented to evaluate the basic principle and technical function of proposed approaches. Further improvements of the technical design and additional clinical testing is required to prove whether the therapeutic outcome can be enhanced by such cooperative strategies.


Evaluation of bovine (Bos indicus) ovarian potential for in vitro embryo production in the Adamawa plateau (Cameroon).
An abattoir study was conducted to evaluate the ovarian potential of 201 local zebu cattle from Ngaoundere, Adamawa region (Cameroon) for in vitro embryo production (IVEP). The ovaries were excised, submerged in normal saline solution (0.9%) and transported to the laboratory for a detailed evaluation. Follicles on each ovary were counted, their diameters (Φ) measured and were grouped into 3 categories: small (Φ < 3 mm), medium (3 ≥ Φ ≤ 8 mm) and large (Φ > 8 mm). Each ovary was then sliced into a petri dish; the oocytes were recovered in Dulbecco's phosphate buffered saline, examined under a stereoscope (x10) and graded into four groups based on the morphology of cumulus oophorus cells and cytoplasmic changes of the oocytes. Grade I (GI): oocytes with more than 4 layers of bunch of compact cumulus cells mass with evenly granulated cytoplasm; grade II (GII): oocyte with at least 2-4 layers of compact cumulus cell mass with evenly granulated cytoplasm; grade III (GIII): oocyte with at least one layer of compact cumulus cell mass with evenly granulated cytoplasm; grade IV (GIV): denuded oocyte with no cumulus cells or incomplete layer of cumulus cell or expanded cells and having dark or unevenly granulated cytoplasm. The effects of both ovarian (ovarian localization, corpus luteum, size and weight of ovary) and non-ovarian factors (breed, age, body condition score (BCS) and pregnancy status of cow) on the follicular population and oocyte recovery rate were determined. There were an average of 16.75±0.83 follicles per ovary. The small, medium and large follicles were 8.39±0.60, 8.14±0.43 and 0.21±0.02 respectively. Oocyte recovery was 10.97±0.43 per ovary (65%). Oocytes graded I, II, III and IV were 3.53±0.19 (32.21%), 2.72±0.15 (24.82%), 2.24±0.15 (20.43%) and 2.47±0.20 (22.54%) respectively. The oocyte quality index was 2.26. Younger non pregnant cows having BCS of 3 and large ovaries presented higher number of follicles and oocyte quality (P < 0.05) compared with other animals. Oocytes with quality (grade I and II) acceptable for IVEP constituted 57.15% of the harvest. This study indicated that factors such as age, pregnancy status, BCS and ovarian size must be taken into account to increase the potential of the ovary for IVEP.


In silico analysis of T-bet activity in peripheral blood mononuclear cells in patients with inflammatory bowel disease (IBD).
T-bet (TBX21) is a transcription factor that regulates T-cell differentiation, and has recently been implicated in the pathogenesis of Crohn's disease (CD). The regulatory networks through which T-bet affects immune function are unknown. An NCBI gene expression profile from patients with CD and controls was analyzed. T-bet transcription factor binding sites and promoter modules were identified using promoter analysis software. Functional correlations between T-bet-containing promoters were determined using data mining and ontological analysis. T-bet expression in CD peripheral blood mononuclear cells (PBMCs) (n=59) was significantly reduced compared to control (n=42) (p<0.0001) and ulcerative colitis PBMCs (n=26), (p=0.005). The promoter regions of all genes differentially-expressed in CD were probed for T-bet Transcription Factor Binding Sites (TFBSs). Twenty-three genes contained transcription-factor binding sites for T-bet; 8 were down-regulated, and 15 were up-regulated in CD-PBMCs. Three genes (S100A16, ABHD3 and EZH1) that were down-regulated in CD-PBMCs contained a complex promoter module consisting of T-bet and EGRF transcription-factor binding sites. Ontological analysis revealed that a significant number of differentially-expressed genes that contain T-bet binding sites are involved in innate immunity (8 genes, Z-score 4.11) and signal transduction (5 genes, Z-score 2.65). This combination of gene expression datasets and promoter analysis has identified a network of genes that contain simple T-bet binding sites, and complex T-bet promoter modules, in their promoter regions. These results implicate a mechanism through which T-bet may influence innate immunity in CD.


Safety syringes can reduce the risk of needlestick injury in venous thromboembolism prophylaxis.
Patients undergoing major orthopaedic surgery of the lower extremities are at high risk of developing venous thromboembolism (VTE). Pharmacologic thromboprophylaxis has greatly reduced the likelihood of VTE. The most effective medications are administered once or twice daily by subcutaneous injection, a drug delivery route associated with an increased risk of needlestick injury. Awareness of the potential lethality of needlestick injuries has increased during the past decade, resulting in the development of national safety guidelines from the Occupational Safety and Health Administration on the handling and management of needles and other sharps. This article reviews the potential risks and costs associated with needlestick injury during the administration of VTE prophylaxis in patients undergoing major orthopaedic surgery. The development of novel anticoagulants and accompanying devices to prevent needlestick injury is also discussed.


The lectin-binding pattern of nucleolin and its interaction with endogenous galectin-3.
Unlike nuclear nucleolin, surface-expressed and cytoplasmic nucleolin exhibit Tn antigen. Here, we show localization-dependent differences in the glycosylation and proteolysis patterns of nucleolin. Our results provide evidence for different paths of nucleolin proteolysis in the nucleus, in the cytoplasm, and on the cell surface. We found that full-length nucleolin and some proteolytic fragments coexist within live cells and are not solely the result of the preparation procedure. Extranuclear nucleolin undergoes N- and O-glycosylation, and unlike cytoplasmic nucleolin, membrane-associated nucleolin is not fucosylated. Here, we show for the first time that nucleolin and endogenous galectin-3 exist in the same complexes in the nucleolus, the cytoplasm, and on the cell surface of melanoma cells. Assessments of the interaction of nucleolin with galectin-3 revealed nucleolar co-localization in interphase, suggesting that galectin-3 may be involved in DNA organization and ribosome biogenesis.


Assessment of the psychometric properties of the AQoL-4D questionnaire in Kannada language for use with adults with hearing loss.
This study aimed to validate the translated (Kannada language) version of the Assessment of Quality of Life-4 Dimensions (AQoL-4D) questionnaire for use in Kannada speaking adults with hearing loss. The study involved a cross-sectional survey design. The original (English) and the translated versions of the AQoL-4D questionnaire along with two other questionnaires, that is, the Hearing Handicap Questionnaire and the Participation Scale were self-administered by the study participants. The Kannada AQoL-4D was filled in twice by roughly 50% of the study sample in two sessions that were 15 d apart. In total, 103 Kannada-English biliterate adults with hearing loss participated in the study. Overall analysis involved testing the factor structure and various psychometric properties including the internal consistency, discriminant validity, convergent validity and possible floor/ceiling effects. The factor analysis indicated a four-factor structure, and the overall results showed acceptable psychometric properties of the scores of the full scale. However, poor internal consistency was obtained for three out of the four subscales extracted from the questionnaire. Based on the internal consistency of the subscales, we recommend using either the full scale or only the first subscale in Kannada speaking adults with hearing loss.


From intestinal permeability to dysmotility: the biobreeding rat as a model for functional gastrointestinal disorders.
Impaired intestinal barrier function, low-grade inflammation and altered neuronal control are reported in functional gastrointestinal disorders. However, the sequence of and causal relation between these events is unclear, necessitating a spontaneous animal model. The aim of this study was to describe the natural history of intestinal permeability, mucosal and neuromuscular inflammation and nitrergic motor neuron function during the lifetime of the BioBreeding (BB) rat. Normoglycemic BB-diabetes prone (DP) and control rats were sacrificed at different ages and jejunum was harvested to characterize intestinal permeability, inflammation and neuromuscular function. Both structural and functional evidence of increased intestinal permeability was found in young BB-DP rats from the age of 50 days. In older animals, starting in the mucosa from 70 days and in half of the animals also in the muscularis propria from 110 days, an inflammatory reaction, characterized by an influx of polymorphonuclear cells and higher myeloperoxidase activity, was observed. Finally, in animals older than 110 days, coinciding with a myenteric ganglionitis, a loss of nitrergic neurons and motor function was demonstrated. In the BB-rat, mucosal inflammatory cell infiltration is preceded by intestinal barrier dysfunction and followed by myenteric ganglionitis and loss of nitrergic function. This sequence supports a primary role for impaired barrier function and provides an insightful model for the pathogenesis of functional gastrointestinal disorders.


Mepolizumab for prednisone-dependent asthma with sputum eosinophilia.
Eosinophilic inflammation, which may be a consequence of interleukin-5 action, is a characteristic feature of some forms of asthma. However, in three previous clinical trials involving patients with asthma, blockade of this cytokine did not result in a significant improvement in outcomes. We studied the prednisone-sparing effect of mepolizumab, a monoclonal antibody against interleukin-5, in a rare subgroup of patients who have sputum eosinophilia and airway symptoms despite continued treatment with prednisone. Secondary objectives were to examine its effect on the number of eosinophils in sputum and blood, symptoms, and airflow limitation. In this randomized, double-blind, parallel-group trial involving patients with persistent sputum eosinophilia and symptoms despite prednisone treatment, we assigned 9 patients to receive mepolizumab (administered in five monthly infusions of 750 mg each) and 11 patients to receive placebo. There were 12 asthma exacerbations in 10 patients who received placebo, 9 of whom had sputum eosinophilia at the time of exacerbation. In comparison, only one patient who received mepolizumab had an asthma exacerbation, and this episode was not associated with sputum eosinophilia (P=0.002). Patients who received mepolizumab were able to reduce their prednisone dose by a mean (+/-SD) of 83.8+/-33.4% of their maximum possible dose, as compared with 47.7+/-40.5% in the placebo group (P=0.04). The use of mepolizumab was associated with a significant decrease in the number of sputum and blood eosinophils. Improvements in eosinophil numbers, asthma control, and forced expiratory volume in 1 second were maintained for 8 weeks after the last infusion. There were no serious adverse events. Mepolizumab reduced the number of blood and sputum eosinophils and allowed prednisone sparing in patients who had asthma with sputum eosinophilia despite prednisone treatment. (ClinicalTrials.gov number, NCT00292877.)


Patent information retrieval: approaching a method and analysing nanotechnology patent collaborations.
Many challenges still remain in the processing of explicit technological knowledge documents such as patents. Given the limitations and drawbacks of the existing approaches, this research sets out to develop an improved method for searching patent databases and extracting patent information to increase the efficiency and reliability of nanotechnology patent information retrieval process and to empirically analyse patent collaboration. A tech-mining method was applied and the subsequent analysis was performed using Thomson data analyser software. The findings show that nations such as Korea and Japan are highly collaborative in sharing technological knowledge across academic and corporate organisations within their national boundaries, and China presents, in some cases, a great illustration of effective patent collaboration and co-inventorship. This study also analyses key patent strengths by country, organisation and technology.


An Iterative CT Reconstruction Algorithm for Fast Fluid Flow Imaging.
The study of fluid flow through solid matter by computed tomography (CT) imaging has many applications, ranging from petroleum and aquifer engineering to biomedical, manufacturing, and environmental research. To avoid motion artifacts, current experiments are often limited to slow fluid flow dynamics. This severely limits the applicability of the technique. In this paper, a new iterative CT reconstruction algorithm for improved a temporal/spatial resolution in the imaging of fluid flow through solid matter is introduced. The proposed algorithm exploits prior knowledge in two ways. First, the time-varying object is assumed to consist of stationary (the solid matter) and dynamic regions (the fluid flow). Second, the attenuation curve of a particular voxel in the dynamic region is modeled by a piecewise constant function over time, which is in accordance with the actual advancing fluid/air boundary. Quantitative and qualitative results on different simulation experiments and a real neutron tomography data set show that, in comparison with the state-of-the-art algorithms, the proposed algorithm allows reconstruction from substantially fewer projections per rotation without image quality loss. Therefore, the temporal resolution can be substantially increased, and thus fluid flow experiments with faster dynamics can be performed.


Classification of drugs based on properties of sodium channel inhibition: a comparative automated patch-clamp study.
There is only one established drug binding site on sodium channels. However, drug binding of sodium channels shows extreme promiscuity: ∼25% of investigated drugs have been found to potently inhibit sodium channels. The structural diversity of these molecules suggests that they may not share the binding site, and/or the mode of action. Our goal was to attempt classification of sodium channel inhibitors by measuring multiple properties of inhibition in electrophysiology experiments. We also aimed to investigate if different properties of inhibition correlate with specific chemical properties of the compounds. A comparative electrophysiological study of 35 compounds, including classic sodium channel inhibitors (anticonvulsants, antiarrhythmics and local anesthetics), as well as antidepressants, antipsychotics and neuroprotective agents, was carried out using rNav1.2 expressing HEK-293 cells and the QPatch automatic patch-clamp instrument. In the multi-dimensional space defined by the eight properties of inhibition (resting and inactivated affinity, potency, reversibility, time constants of onset and offset, use-dependence and state-dependence), at least three distinct types of inhibition could be identified; these probably reflect distinct modes of action. The compounds were clustered similarly in the multi-dimensional space defined by relevant chemical properties, including measures of lipophilicity, aromaticity, molecular size, polarity and electric charge. Drugs of the same therapeutic indication typically belonged to the same type. We identified chemical properties, which were important in determining specific properties of inhibition. State-dependence correlated with lipophilicity, the ratio of the neutral form of molecules, and aromaticity: We noticed that the highly state dependent inhibitors had at least two aromatic rings, logP>4.0, and pKa<8.0. The correlations of inhibition properties both with chemical properties and therapeutic profiles would not have been evident through the sole determination of IC(50); therefore, recording multiple properties of inhibition may allow improved prediction of therapeutic usefulness.


Utility of a Lateral Flow Immunoassay (LFI) to Detect Burkholderia pseudomallei in Soil Samples.
Culture is the gold standard for the detection of environmental B. pseudomallei. In general, soil specimens are cultured in enrichment broth for 2 days, and then the culture broth is streaked on an agar plate and incubated further for 7 days. However, identifying B. pseudomallei on the agar plates among other soil microbes requires expertise and experience. Here, we evaluate a lateral flow immunoassay (LFI) developed to detect B. pseudomallei capsular polysaccharide (CPS) in clinical samples as a tool to detect B. pseudomallei in environmental samples. First, we determined the limit of detection (LOD) of LFI for enrichment broth of the soil specimens. Soil specimens (10 grams/specimen) culture negative for B. pseudomallei were spiked with B. pseudomallei ranging from 10 to 105 CFU, and incubated in 10 ml of enrichment broth in air at 40°C. Then, on day 2, 4 and 7 of incubation, 50 μL of the upper layer of the broth were tested on the LFI, and colony counts to determine quantity of B. pseudomallei in the broth were performed. We found that all five soil specimens inoculated at 10 CFU were negative by LFI on day 2, but four of those five specimens were LFI positive on day 7. The LOD of the LFI was estimated to be roughly 3.8x106 CFU/ml, and culture broth on day 7 was selected as the optimal sample for LFI testing. Second, we evaluated the utility of the LFI by testing 105 soil samples from Northeast Thailand. All samples were also tested by standard culture and quantitative PCR (qPCR) targeting orf2. Of 105 soil samples, 35 (33%) were LFI positive, 25 (24%) were culture positive for B. pseudomallei, and 79 (75%) were qPCR positive. Of 11 LFI positive but standard culture negative specimens, six were confirmed by having the enrichment broth on day 7 culture positive for B. pseudomallei, and an additional three by qPCR. The LFI had 97% (30/31) sensitivity to detect soil specimens culture positive for B. pseudomallei. The LFI can be used to detect B. pseudomallei in soil samples, and to select which samples should be sent to reference laboratories or proceed further for bacterial isolation and confirmation. This could considerably decrease laboratory workload and assist the development of a risk map for melioidosis in resource-limited settings.


Curvatures with uncertainties derived in conformal space to characterize tendon microstructure.
There is a growing demand for non-invasive methods to diagnose tendon injuries and monitor the healing processes of their repair. To date there is limited knowledge on their structure and function and the interlink between these. One of the potential targets in this investigation is the extracellular matrix (ECM) that captures its structural changes. Recently we reported on the assessment tendon damage on a macroscopic level from high field MR signals. In this paper, we present a methodology that enables structural description on a microscopic level. We derived curvature values from the conformal monogenic signal, which however can become unreliable in the presence of noise. To account for this we use non parametric noise properties and a 1D feature based uncertainty measure in an iterative framework using Hidden Markov Measure Field (HMMF). The proposed method reveals that curvature values derived from normal tendon tissue microscopy images are higher and more homogenous than curvature values derived from the damaged tendon images.


Nitrogen management is essential to prevent tropical oil palm plantations from causing ground-level ozone pollution.
More than half the world's rainforest has been lost to agriculture since the Industrial Revolution. Among the most widespread tropical crops is oil palm (Elaeis guineensis): global production now exceeds 35 million tonnes per year. In Malaysia, for example, 13% of land area is now oil palm plantation, compared with 1% in 1974. There are enormous pressures to increase palm oil production for food, domestic products, and, especially, biofuels. Greater use of palm oil for biofuel production is predicated on the assumption that palm oil is an "environmentally friendly" fuel feedstock. Here we show, using measurements and models, that oil palm plantations in Malaysia directly emit more oxides of nitrogen and volatile organic compounds than rainforest. These compounds lead to the production of ground-level ozone (O(3)), an air pollutant that damages human health, plants, and materials, reduces crop productivity, and has effects on the Earth's climate. Our measurements show that, at present, O(3) concentrations do not differ significantly over rainforest and adjacent oil palm plantation landscapes. However, our model calculations predict that if concentrations of oxides of nitrogen in Borneo are allowed to reach those currently seen over rural North America and Europe, ground-level O(3) concentrations will reach 100 parts per billion (10(9)) volume (ppbv) and exceed levels known to be harmful to human health. Our study provides an early warning of the urgent need to develop policies that manage nitrogen emissions if the detrimental effects of palm oil production on air quality and climate are to be avoided.


Functional equivalence of stem cell and stem cell-derived extracellular vesicle transplantation to repair the irradiated brain.
Cranial radiotherapy, although beneficial for the treatment of brain tumors, inevitably leads to normal tissue damage that can induce unintended neurocognitive complications that are progressive and debilitating. Ionizing radiation exposure has also been shown to compromise the structural integrity of mature neurons throughout the brain, an effect believed to be at least in part responsible for the deterioration of cognitive health. Past work has shown that cranially transplanted human neural stem cells (hNSCs) or their extracellular vesicles (EVs) afforded long-term beneficial effects on many of these cognitive decrements. To provide additional insight into the potential neuroprotective mechanisms of cell-based regenerative strategies, we have analyzed hippocampal neurons for changes in structural integrity and synaptic remodeling after unilateral and bilateral transplantation of hNSCs or EVs derived from those same cells. Interestingly, hNSCs and EVs similarly afforded protection to host neurons, ameliorating the impact of irradiation on dendritic complexity and spine density for neurons present in both the ipsilateral and contralateral hippocampi 1 month following irradiation and transplantation. These morphometric improvements were accompanied by increased levels of glial cell-derived growth factor and significant attenuation of radiation-induced increases in postsynaptic density protein 95 and activated microglia were found ipsi- and contra-lateral to the transplantation sites of the irradiated hippocampus treated with hNSCs or hNSC-derived EVs. These findings document potent far-reaching neuroprotective effects mediated by grafted stem cells or EVs adjacent and distal to the site of transplantation and support their potential as therapeutic agents to counteract the adverse effects of cranial irradiation.


Identifying neurobiological phenotypes associated with alcohol use disorder severity.
Although numerous studies provide general support for the importance of genetic factors in the risk for alcohol use disorders (AUDs), candidate gene and genome-wide studies have yet to identify a set of genetic variations that explain a significant portion of the variance in AUDs. One reason is that alcohol-related phenotypes used in genetic studies are typically based on highly heterogeneous diagnostic categories. Therefore, identifying neurobiological phenotypes related to neuroadaptations that drive the development of AUDs is critical for the future success of genetic and epigenetic studies. One such neurobiological phenotype is the degree to which exposure to alcohol taste cues recruits the basal ganglia, prefrontal cortex, and motor areas, all of which have been shown to have a critical role in addictive behaviors in animal studies. To that end, this study was designed to examine whether cue-elicited responses of these structures are associated with AUD severity in a large sample (n=326) using voxelwise and functional connectivity measures. Results suggested that alcohol cues significantly activated dorsal striatum, insula/orbitofrontal cortex, anterior cingulate cortex, and ventral tegmental area. AUD severity was moderately correlated with regions involved in incentive salience such as the nucleus accumbens and amygdala, and stronger relationships with precuneus, insula, and dorsal striatum. The findings indicate that AUDs are related to neuroadaptations in these regions and that these measures may represent important neurobiological phenotypes for subsequent genetic studies.


Growth hormone-induced changes in myofibrillar protein breakdown in hypopituitary children.
1. Creatinine and N tau-methylhistidine excretion rates have been measured in 13 hypopituitary children to calculate the body muscle contents and rates of myofibrillar protein breakdown. Analyses have been made during periods of growth hormone withdrawal and subsequent administration. 2. The creatinine excretion rate was lower in the hypopituitary children, indicating a lower muscle content per kg body weight. This difference persisted even in children who had received growth hormone for several years. 3. Excretion of N tau-methylhistidine was reduced by the administration of growth hormone. 4. The fractional breakdown rate of myofibrillar protein, as calculated from the N tau-methylhistidine to creatinine molar excretion ratio, averaged 1.76%/day in the four youngest children during growth hormone withdrawal. This was significantly higher than for control children of a similar age (P less than 0.02) and was reduced to the normal rate of 1.47%/day by growth hormone administration. 5. In older children the fractional rate of myofibrillar protein degradation remained in the normal range irrespective of growth hormone treatment. 6. These results are discussed in the context of the anabolic effects of growth hormone on muscle being partly explained by its action to decrease rates of protein breakdown.


A novel 53-kDa nodulin of the symbiosome membrane of soybean nodules, controlled by Bradyrhizobium japonicum.
A nodule-specific 53-kDa protein (GmNOD53b) of the symbiosome membrane from soybean was isolated and its LysC digestion products were microsequenced. cDNA clones of this novel nodulin, obtained from cDNA library screening with an RT-PCR (reverse-transcriptase polymerase chain reaction)-generated hybridization probe exhibited no homology to proteins identified so far. The expression of GmNOD53b coincides with the onset of nitrogen fixation. Therefore, it is a late nodulin. Among other changes, the GmNOD53b is significantly reduced in nodules infected with the Bradyrhizobium japonicum mutant 184 on the protein level as well as on the level of mRNA expression, compared with the wild-type infected nodules. The reduction of GmNOD53b mRNA is related to an inactivation of the sipF gene in B. japonicum 184, coding for a functionally active signal peptidase.


Consumer Understanding, Preferences, and Responses to Different Versions of Drug Safety Messages in the United States: A Randomized Controlled Trial.
As part of its mission, the US Food and Drug Administration (FDA) communicates with the public regularly about the benefits and risks of prescription and over-the-counter (OTC) drugs. Effectively communicating risk, however, is a significant public health challenge. To better understand how different populations understand information communicated by the FDA about drug safety, we conducted a randomized experiment to examine comprehension and other measures of effectiveness of drug safety messages that occurred in a post-market surveillance phase. We used an Internet panel survey of 1244 consumers, of whom 58% used prescription drugs in the past year. Half of the sample panel was randomized to read a previous FDA Drug Safety Communication (DSC) with the drug name changed, and the other half was randomized to read a revised version of the same DSC. We examined how making certain modifications to the way drug risk information is communicated has an impact on comprehension and behavioral intentions, including the user's likelihood of discontinuing the drug. We also studied how comprehension varied by respondent characteristics, health literacy skills, risk perceptions, and trust in the message. Based on a five-item comprehension index, the revised version of the message was associated with significantly greater comprehension of the information relative to the standard version (63 vs 52% correct, p < 0.001). Significantly more respondents found the revised version to be clear (82 vs 73%, p < 0.000), while fewer in that group reported learning something new (78% vs 84%, p = 0.015). No significant differences emerged between the two groups in terms of the message being informative, convincing, or helpful. We found no significant differences between the two groups in terms of behavioral intentions, risk perception, and trust. We found that making plain language changes to the DSC significantly increased consumers' level of comprehension of its content, providing support for ongoing use and further exploration of these strategies in pharmacovigilance communication research. The study findings have important implications for future drug safety and other communication messages related to prescription drugs.


Adaptive Gaussian Process Approximation for Bayesian Inference with Expensive Likelihood Functions.
We consider Bayesian inference problems with computationally intensive likelihood functions. We propose a Gaussian process (GP)-based method to approximate the joint distribution of the unknown parameters and the data, built on recent work (Kandasamy, Schneider, & Póczos, 2015). In particular, we write the joint density approximately as a product of an approximate posterior density and an exponentiated GP surrogate. We then provide an adaptive algorithm to construct such an approximation, where an active learning method is used to choose the design points. With numerical examples, we illustrate that the proposed method has competitive performance against existing approaches for Bayesian computation.


Hypergonadotropic hypogonadism in spinocerebellar ataxia type 2: a case report.
The association between cerebellar ataxia and hypogonadism is seen rarely and is not well recognized. Spinocerebellar ataxia (SCA) is an autosomal dominantly inherited, progressive ataxia disorder, and SCA type 2 (SCA2) characteristically presents with a highly variable phenotype with multisystemic involvement. Although the clinical spectrum of SCA2 is broad, hypogonadism has not been reported as an accompanying symptom. To report a case study that describes hypergonadotropic hypogonadism as a non-neurological manifestation of cerebellar ataxia in a patient with a hereditary trinucleotide repeat expansion disorder, SCA2. Case report of a man admitted to an academic medical center. A 45-year-old man with a history of azoospermia in work-up for infertility was admitted for evaluation of a left-side hand tremor, instability on walking and impaired balance. Upon physical examination, the patient had a micropenis about 3 cm in length and had decreased testicular size (12 cc each) on orchidometry, but normal secondary sexual characteristics and average stature. Laboratory tests showed the presence of hypergonadotropic hypogonadism. A brain magnetic resonance imaging scan showed marked atrophy involving both the cerebellum and pons. Genetic analysis for hereditary ataxia demonstrated the presence of a 37 CAG triplet expansion in the mutated allele (genotype 22/37) in the SCA2 gene, confirming the diagnosis of SCA2. The present study suggests that a common genetic implication may be shared between these neurologic and non-neurologic signs, and there may be various associations between these heterogeneous manifestations. The clinical spectrum of the SCA2 should be widened, and further data collection is needed to elucidate the relationship among the clinical manifestations.


Correlation Between Euro NCAP Pedestrian Test Results and Injury Severity in Injury Crashes with Pedestrians and Bicyclists in Sweden.
Pedestrians and bicyclists account for a significant share of deaths and serious injuries in the road transport system. The protection of pedestrians in car-to-pedestrian crashes has therefore been addressed by friendlier car fronts and since 1997, the European New Car Assessment Program (Euro NCAP) has assessed the level of protection for most car models available in Europe. In the current study, Euro NCAP pedestrian scoring was compared with real-life injury outcomes in car-to-pedestrian and car-tobicyclist crashes occurring in Sweden. Approximately 1200 injured pedestrians and 2000 injured bicyclists were included in the study. Groups of cars with low, medium and high pedestrian scores were compared with respect to pedestrian injury severity on the Maximum Abbreviated Injury Scale (MAIS)-level and risk of permanent medical impairment (RPMI). Significant injury reductions to both pedestrians and bicyclists were found between low and high performing cars. For pedestrians, the reduction of MAIS2+, MAIS3+, RPMI1+ and RPMI10+ ranged from 20-56% and was significant on all levels except for MAIS3+ injuries. Pedestrian head injuries had the highest reduction, 80-90% depending on level of medical impairment. For bicyclist, an injury reduction was only observed between medium and high performing cars. Significant injury reductions were found for all body regions. It was also found that cars fitted with autonomous emergency braking including pedestrian detection might have a 60-70% lower crash involvement than expected. Based on these results, it was recommended that pedestrian protection are implemented on a global scale to provide protection for vulnerable road users worldwide.


A humanized mouse model of liver fibrosis following expansion of transplanted hepatic stellate cells.
Hepatic stellate cells (HSCs) are major contributors to liver fibrosis, as hepatic injuries may cause their transdifferentiation into myofibroblast-like cells capable of producing excessive extracellular matrix proteins. Also, HSCs can modulate engraftment of transplanted hepatocytes and contribute to liver regeneration. Therefore, understanding the biology of human HSCs (hHSCs) is important, but effective methods have not been available to address their fate in vivo. To investigate whether HSCs could engraft and repopulate the liver, we transplanted GFP-transduced immortalized hHSCs into immunodeficient NOD/SCID mice. Biodistribution analysis with radiolabeled hHSCs showed that after intrasplenic injection, the majority of transplanted cells rapidly translocated to the liver. GFP-immunohistochemistry demonstrated that transplanted hHSCs engrafted alongside hepatic sinusoids. Prior permeabilization of the sinusoidal endothelial layer with monocrotaline enhanced engraftment of hHSCs. Transplanted hHSCs remained engrafted without relevant proliferation in the healthy liver. However, after CCl4 or bile duct ligation-induced liver damage, transplanted hHSCs expanded and contributed to extracellular matrix production, formation of bridging cell-septae and cirrhosis-like hepatic pseudolobules. CCl4-induced injury recruited hHSCs mainly to zone 3, whereas after bile duct ligation, hHSCs were mainly in zone 1 of the liver lobule. Transplanted hHSCs neither transdifferentiated into other cell types nor formed tumors in these settings. In conclusion, a humanized mouse model was generated by transplanting hHSCs, which proliferated during hepatic injury and inflammation, and contributed to liver fibrosis. The ability to repopulate the liver with transplanted hHSCs will be particularly significant for mechanistic studies of cell-cell interactions and fibrogenesis within the liver.


Moderators of response to cognitive behavioural therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care.
Stratified medicine aims to improve clinical and cost-effectiveness by identifying moderators of treatment that indicate differential response to treatment. Cognitive behavioural therapy (CBT) is often offered as a 'next-step' for patients who have not responded to antidepressants, but no research has examined moderators of response to CBT in this population. We aimed, therefore, to identify moderators of response to CBT in treatment resistant depression. We used linear regression to test for interactions between treatment effect and 14 putative moderator variables using data from the CoBalT randomised controlled trial. This trial examined the effectiveness of CBT given in addition to usual care (n=234) compared with usual care alone (n=235) for primary care patients with treatment resistant depression. Age was the only variable with evidence for effect modification (p Value for interaction term=0.012), with older patients benefiting the most from CBT. We found no evidence of effect modification by any other demographic, life, illness, personality trait, or cognitive variable (p≥0.2). Given the largely null findings, a stratified approach that might limit offering CBT is premature; CBT should be offered to all individuals where antidepressant medication has failed.


A model for the European platform for rare disease registries.
The current situation of rare disease (RD) registries is rather heterogeneous, and new ways to support the registration of RD patients are being sought in the European Union (EU) and the US. The project 'Building Consensus and Synergies for the EU Registration of RD Patients', funded by the EU, aimed to define a model platform for EU RD registries. A number of surveys and extensive consultations among registry stakeholders have been carried out to study how the platform can best fulfill their needs. This web-based, multidisease and multipurpose platform is intended to provide a number of functions: a metadata and data repository function supporting the planning of research studies and the production of predefined outputs for the funding organizations and the public, provision of tools and resources of use to registries, promotion of registration and networking among patients and professionals. Its main impact is expected to be on data and procedures standardization, on the establishment of new registries, on the sustainability of the smaller ones, and on the registration of those RDs for which a dedicated registry is not sustainable, e.g. ultra-rare diseases or diseases for which there is no special research, clinical or economic interest. It will also impact on the production of sounder information on RD and RD-dedicated health systems, by promoting registry data comparability and quality.


Proton MRI as a noninvasive tool to assess elastase-induced lung damage in spontaneously breathing rats.
Elastase-induced changes in lung morphology and function were detected in spontaneously breathing rats using conventional proton MRI at 4.7 T. A single dose of porcine pancreatic elastase (75 U/100 g body weight) or vehicle (saline) was administered intratracheally (i.t.) to male Brown Norway (BN) rats. MRI fluid signals were detected in the lungs 24 hr after administration of elastase and resolved within 2 weeks. These results correlated with perivascular edema and cellular infiltration observed histologically. Reductions in MRI signal intensity of the lung parenchyma, and increases in lung volume were detected as early as 2 weeks following elastase administration and remained uniform throughout the study, which lasted 8 weeks. Observations were consistent with air trapping resulting from emphysema detected histologically. In a separate experiment, animals were treated daily intraperitoneally (i.p.) with all-trans-retinoic acid (ATRA; 500 microg/kg body weight) or its vehicle (triglyceride oil) starting on day 21 after elastase administration and continuing for 12 days. Under these conditions, ATRA did not elicit a reversal of elastase-induced lung damage as measured by MRI and histology. The present approach complements other validated applications of proton MRI in experimental lung research as a method for assessing drugs in rat models of respiratory diseases.


Natural variability of Greenland climate, vegetation, and ice volume during the past million years.
The response of the Greenland ice sheet to global warming is a source of concern notably because of its potential contribution to changes in the sea level. We demonstrated the natural vulnerability of the ice sheet by using pollen records from marine sediment off southwest Greenland that indicate important changes of the vegetation in Greenland over the past million years. The vegetation that developed over southern Greenland during the last interglacial period is consistent with model experiments, suggesting a reduced volume of the Greenland ice sheet. Abundant spruce pollen indicates that boreal coniferous forest developed some 400,000 years ago during the "warm" interval of marine isotope stage 11, providing a time frame for the development and decline of boreal ecosystems over a nearly ice-free Greenland.


Formicine ants: An arthropod source for the pumiliotoxin alkaloids of dendrobatid poison frogs.
A remarkable diversity of bioactive lipophilic alkaloids is present in the skin of poison frogs and toads worldwide. Originally discovered in neotropical dendrobatid frogs, these alkaloids are now known from mantellid frogs of Madagascar, certain myobatrachid frogs of Australia, and certain bufonid toads of South America. Presumably serving as a passive chemical defense, these alkaloids appear to be sequestered from a variety of alkaloid-containing arthropods. The pumiliotoxins represent a major, widespread, group of alkaloids that are found in virtually all anurans that are chemically defended by the presence of lipophilic alkaloids. Identifying an arthropod source for these alkaloids has been a considerable challenge for chemical ecologists. However, an extensive collection of neotropical forest arthropods has now revealed a putative arthropod source of the pumiliotoxins. Here we report on the presence of pumiliotoxins in formicine ants of the genera Brachymyrmex and Paratrechina, as well as the presence of these ants in the stomach contents of the microsympatric pumiliotoxin-containing dendrobatid frog, Dendrobates pumilio. These pumiliotoxins are major alkaloids in D. pumilio, and Brachymyrmex and Paratrechina ants now represent the only known dietary sources of these toxic alkaloids. These findings further support the significance of ant-specialization and alkaloid sequestration in the evolution of bright warning coloration in poison frogs and toads.


Wheat root systems as a breeding target for climate resilience.
In the coming decades, larger genetic gains in yield will be necessary to meet projected demand, and this must be achieved despite the destabilizing impacts of climate change on crop production. The root systems of crops capture the water and nutrients needed to support crop growth, and improved root systems tailored to the challenges of specific agricultural environments could improve climate resiliency. Each component of root initiation, growth and development is controlled genetically and responds to the environment, which translates to a complex quantitative system to navigate for the breeder, but also a world of opportunity given the right tools. In this review, we argue that it is important to know more about the 'hidden half' of crop plants and hypothesize that crop improvement could be further enhanced using approaches that directly target selection for root system architecture. To explore these issues, we focus predominantly on bread wheat (Triticum aestivum L.), a staple crop that plays a major role in underpinning global food security. We review the tools available for root phenotyping under controlled and field conditions and the use of these platforms alongside modern genetics and genomics resources to dissect the genetic architecture controlling the wheat root system. To contextualize these advances for applied wheat breeding, we explore questions surrounding which root system architectures should be selected for, which agricultural environments and genetic trait configurations of breeding populations are these best suited to, and how might direct selection for these root ideotypes be implemented in practice.


Intravenous magnesium for cardiac arrhythmias: jack of all trades.
Intravenous magnesium has been used to prevent and treat many different types of cardiac arrhythmia. It has diverse electrophysiological actions on the conduction system of the heart; including prolonging sinus node recovery time, and reducing automaticity, atrioventricular nodal conduction, antegrade and retrograde conduction over an accessory pathway, and His-ventricular conduction. Intravenous magnesium can also homogenise transmural ventricular repolarisation. Because of its unique and diverse electrophysiological actions, intravenous magnesium has been reported to be useful in preventing atrial fibrillation and ventricular arrhythmias after cardiac and thoracic surgery; in reducing the ventricular response in acute onset atrial fibrillation, including for patients with Wolff-Parkinson-White syndrome; in the treatment of digoxin induced supraventricular and ventricular arrhythmias, multifocal atrial tachycardia, and polymorphic ventricular tachycardia or ventricular fibrillation from drug overdoses. Intravenous magnesium is, however, not useful in monomorphic ventricular tachycardia and shock-resistant ventricular fibrillation. Large randomised controlled studies are needed to confirm whether intravenous magnesium can improve patient centre outcomes in different cardiac arrhythmias.


RNA editing, DNA recoding and the evolution of human cognition.
RNA editing appears to be the major mechanism by which environmental signals overwrite encoded genetic information to modify gene function and regulation, particularly in the brain. We suggest that the predominance of Alu elements in the human genome is the result of their evolutionary co-adaptation as a modular substrate for RNA editing, driven by selection for higher-order cognitive function. We show that RNA editing alters transcripts from loci encoding proteins involved in neural cell identity, maturation and function, as well as in DNA repair, implying a role for RNA editing not only in neural transmission and network plasticity but also in brain development, and suggesting that communication of productive changes back to the genome might constitute the molecular basis of long-term memory and higher-order cognition.


Variant cell lines selected for alterations in the function of the hyaluronan receptor CD44 show differences in glycosylation.
CD44 is a major cell surface receptor for the extracellular matrix glycosaminoglycan hyaluronan (HA). However, the ability of CD44 to bind ligand is strictly regulated. Three activation states of CD44 have been demonstrated: (a) inactive; (b) inducible (by certain CD44-specific mAb); and (c) constitutively active. Starting with two parental cell lines expressing CD44 in the inactive state, a pre-B cell (RAW 253) and a fibroblast (L cells), we used fluorescence-activated cell sorting with fluorescein-conjugated hyaluronan in the presence of inducing mAb to derive variant cell lines with CD44 in the inducible state. Constitutively active derivatives were isolated from the inducible variants by a further round of fluorescence-activated cell sorting in the absence of inducing antibody. However, constitutively active variants could not be isolated directly from parental cells expressing CD44 in the inactive state. These results suggest that two genetic events must occur to obtain an active CD44-HA receptor from an inactive receptor. Variant and parental cell-derived CD44 molecules exhibited differences in migration on sodium dodecyl sulfate-polyacrylamide gel electrophoresis that were partly attributable to differences in N-linked glycosylation. Furthermore, culture in tunicamycin for 2-3 d converted parental and inducible cell lines into cells showing constitutive CD44-mediated HA binding. Also, removal of cell surface glycosaminoglycan chains by culture of cells in p-nitrophenyl beta-D-xylopyranoside or treatment with chondroitinase ABC resulted in conversion of cells with an inactive CD44 receptor to an inducible state. These results indicate that carbohydrate side chains of CD44 and/or other molecules on the cell surface that interact with CD44 are potentially involved in regulating the HA-binding function of CD44 on the cell surface.


Plant powder teabags: a novel and practical approach to resolve culturability and diversity of rhizobacteria.
We have developed teabags packed with dehydrated plant powders, without any supplements, for preparation of plant infusions necessary to develop media for culturing rhizobacteria. These bacteria are efficiently cultivated on such plant teabag culture media, with better progressive in situ recoverability compared to standard chemically synthetic culture media. Combining various plant-based culture media and incubation conditions enabled us to resolve unique denaturing gradient gel electrophoresis (DGGE) bands that were not resolved by tested standard culture media. Based on polymerase chain reaction PCR-DGGE of 16S rDNA fingerprints and sequencing, the plant teabag culture media supported higher diversity and significant increases in the richness of endo-rhizobacteria, namely Gammaproteobacteria (Enterobacteriaceae) and predominantly Alphaproteobacteria (Rhizobiaceae). This culminated in greater retrieval of the rhizobacteria taxa associated with the plant roots. We conclude that the plant teabag culture medium by itself, without any nutritional supplements, is sufficient and efficient for recovering and mirroring the complex and diverse communities of rhizobacteria. Our message to fellow microbial ecologists is: simply dehydrate your plant canopy, teabag it and soak it to prepare your culture media, with no need for any additional supplementary nutrients.


Analysis of electro-permeation of hydrogen in metallic alloys.
A reaction-diffusion type modelling framework is presented to analyse both electro-permeation (EP) and thermal desorption spectrometry (TDS) measurements of hydrogen in metallic alloys. It is assumed that the kinetics of hydrogen motion is governed by diffusion through the lattice, along with trapping/detrapping at specific sites such as dislocations, grain boundaries, etc. It is shown that the trapping and detrapping rates are typically much faster than the diffusion rate, and consequently a simplification of the governing equations suffices such that local equilibrium exists between lattice and trapped hydrogen. Using this local equilibrium assumption, we then present an asymptotic analysis of the governing kinetic equation for the EP test. This asymptotic analysis reveals that four regimes of behaviour exist, ranging from negligible trapping to the complete filling of deep traps. The analysis suggests that EP tests should be so-arranged that three regimes of behaviour are spanned, in order to extract the relevant material properties associated with hydrogen transport. The numerical solutions presented in this study support the asymptotic analysis. The hydrogen kinetics framework is also deployed to analyse both EP and TDS tests on the same martensitic steel. The EP measurements all lie in regime I and are thus insufficient to uniquely determine both the trap density and binding energy. Reasonable agreement is obtained between measurements and numerical predictions of TDS tests using parameters estimated from the EP tests. Further improvements in measurements are required to confirm the fidelity of this modelling approach.This article is part of the themed issue 'The challenges of hydrogen and metals'.


Empirical support for higher-order theories of conscious awareness.
Higher-order theories of consciousness argue that conscious awareness crucially depends on higher-order mental representations that represent oneself as being in particular mental states. These theories have featured prominently in recent debates on conscious awareness. We provide new leverage on these debates by reviewing the empirical evidence in support of the higher-order view. We focus on evidence that distinguishes the higher-order view from its alternatives, such as the first-order, global workspace and recurrent visual processing theories. We defend the higher-order view against several major criticisms, such as prefrontal activity reflects attention but not awareness, and prefrontal lesion does not abolish awareness. Although the higher-order approach originated in philosophical discussions, we show that it is testable and has received substantial empirical support.


Immunohistochemistry, histopathology and ultrastructure of Gasterosteus aculeatus tissues infected with Glugea anomala.
Immunohistochemical and histopathological studies were conducted on a population of 3-spined sticklebacks Gasterosteus aculeatus (L.) from Loch Airthrey (Stirling, Scotland) naturally infected with the microsporean Glugea anomala (Moniez 1887). Of the 55 host specimens that were examined, 16 (29.09%) were infected, the intensity of infection ranging from 1 to 4 xenomas per fish, which were principally located within the central portion of the body lateral flank musculature. All 32 G. anomala xenomas examined were mature, their diameter ranging from 936 to 2232 Pum, and their walls of presented a laminar structure. Subcutaneously situated xenomas protruded from the fish body surface, whilst xenomas encountered within the intestine were seen to cause distortion. Light and electron microscopical observations confirmed a host cellular reaction around the xenoma, seen by the presence of eosinophile granule cells (EGCs), and some neutrophils. The occurrences of rodlet cells among the intestinal epithelial cells, and in close proximity to the xenoma wall, were observed in certain specimens. Outside the xenoma wall, macrophage aggregates (MAs) were commonly encountered. Within the xenoma wall, the presence of eosinophile granular cells immunoreactive to the anti-serotonin serum was also recorded. Further immunohistochemical tests revealed that a high number of nerve fibres running along the white lateral muscle fibres were immunoreactive to bombesin-, galanin-, and leu-enkephalin-antisera. Nerve fibres containing bombesin- and leu-enkephalin-like substances were also observed in the connective inflammatory tissue around the protozoan cyst, while neurons in the spinal ganglia were immunoreactive to met-enkephalin, and serotonin antisera. The control for the specificity of immunohistochemical reactions was performed using preabsorption tests of each antiserum with the corresponding antigen, and no immunoreactivity was noticed. The data presented are discussed in relation to the occurrence of G. anomala, which alters the pattern of nerve fibres present in the host. Specifically, the protozoan induces a response in the stickleback nervous system, the reaction of which is revealed through the application of immunohistochemical techniques.


Antinociceptive activity of transient receptor potential channel TRPV1, TRPA1, and TRPM8 antagonists in neurogenic and neuropathic pain models in mice.
The aim of this research was to assess the antinociceptive activity of the transient receptor potential (TRP) channel TRPV1, TRPM8, and TRPA1 antagonists in neurogenic, tonic, and neuropathic pain models in mice. For this purpose, TRP channel antagonists were administered into the dorsal surface of a hind paw 15 min before capsaicin, allyl isothiocyanate (AITC), or formalin. Their antiallodynic and antihyperalgesic efficacies after intraperitoneal administration were also assessed in a paclitaxel-induced neuropathic pain model. Motor coordination of paclitaxel-treated mice that received these TRP channel antagonists was investigated using the rotarod test. TRPV1 antagonists, capsazepine and SB-366791, attenuated capsaicin-induced nociceptive reaction in a concentration-dependent manner. At 8 µg/20 µl, this effect was 51% (P<0.001) for capsazepine and 37% (P<0.05) for SB-366791. A TRPA1 antagonist, A-967079, reduced pain reaction by 48% (P<0.05) in the AITC test and by 54% (P<0.001) in the early phase of the formalin test. The test compounds had no influence on the late phase of the formalin test. In paclitaxel-treated mice, they did not attenuate heat hyperalgesia but N-(3-aminopropyl)-2-{[(3-methylphenyl)methyl]oxy}-N-(2-thienylmethyl) benzamide hydrochloride salt (AMTB), a TRPM8 antagonist, reduced cold hyperalgesia and tactile allodynia by 31% (P<0.05) and 51% (P<0.01), respectively. HC-030031, a TRPA1 channel antagonist, attenuated tactile allodynia in the von Frey test (62%; P<0.001). In conclusion, distinct members of TRP channel family are involved in different pain models in mice. Antagonists of TRP channels attenuate nocifensive responses of neurogenic, tonic, and neuropathic pain, but their efficacies strongly depend on the pain model used.


Hypertonic saline for treating raised intracranial pressure: literature review with meta-analysis.
Currently, mannitol is the recommended first choice for a hyperosmolar agent for use in patients with elevated intracranial pressure (ICP). Some authors have argued that hypertonic saline (HTS) might be a more effective agent; however, there is no consensus as to appropriate indications for use, the best concentration, and the best method of delivery. To answer these questions better, the authors performed a review of the literature regarding the use of HTS for ICP reduction. A PubMed search was performed to locate all papers pertaining to HTS use. This search was then narrowed to locate only those clinical studies relating to the use of HTS for ICP reduction. A total of 36 articles were selected for review. Ten were prospective randomized controlled trials (RCTs), 1 was prospective and nonrandomized, 15 were prospective observational trials, and 10 were retrospective trials. The authors did not distinguish between retrospective observational studies and retrospective comparison trials. Prospective studies were considered observational if the effects of a treatment were evaluated over time but not compared with another treatment. The available data are limited by low patient numbers, limited RCTs, and inconsistent methods between studies. However, a greater part of the data suggest that HTS given as either a bolus or continuous infusion can be more effective than mannitol in reducing episodes of elevated ICP. A meta-analysis of 8 prospective RCTs showed a higher rate of treatment failure or insufficiency with mannitol or normal saline versus HTS.


Antibody-based immunosuppressive agents for corneal transplantation.
The progress in antibody engineering over the last 20 years has created the tools for the development of novel antibody-based drugs and constructs, such as small antibody fragments, suitable for topical administration. In rheumatology, oncology, transplantation medicine and ophthalmology, therapeutic antibody constructs, and antibody fragments have been responsible for the clinical progress seen over the last decade. Although antibody-based therapies have become a well-established immunosuppressive option in solid organ transplantation, there are only very few reports with regard to corneal transplantation. The following review explains some of the important aspects of engineered antibody-based therapeutic agents and summarises the current use of such immunosuppressive therapies in transplantation medicine and corneal transplantation.


Extreme prematurity, growth and neurodevelopment at 8 years: a cohort study.
Infants born extremely preterm (EP, <28 weeks' gestation) exhibit poorer growth and neurodevelopmental impairment in early childhood compared with their term-born peers. Whether poor growth persists and whether associations of growth with neurodevelopmental functioning have changed in the decades since the introduction of surfactant are not well described. This study aims to (1) compare growth from birth to 2 years then 8 years in children born EP between three different eras, and (2) investigate the associations of growth from birth to 2 years then 8 years with cognitive, academic, executive and motor function at 8 years, and if associations have changed over time. Prospective observational cohort studies in the State of Victoria, Australia in three discrete eras: 1991-1992, 1997 and 2005. EP children had weight and head circumference measured at birth, and weight, head circumference and height at 2 and 8 years. Cognitive ability, academic performance, executive function and motor skills were assessed at 8 years, corrected for prematurity. 499/546 (91%) of surviving EP children were fully assessed at 8 years. Growth in children born EP did not differ substantially between eras and associations between growth and neurodevelopment did not change over time. Overall, better weight and head growth from birth to 2 years were associated with improved neurodevelopment at 8 years. Growth of children born EP has not improved in more recent eras. Better early head and weight growth are associated with improved neurodevelopment in mid-childhood.


A phenome-wide association study of a lipoprotein-associated phospholipase A2 loss-of-function variant in 90 000 Chinese adults.
Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been implicated in development of atherosclerosis; however, recent randomized trials of Lp-PLA2 inhibition reported no beneficial effects on vascular diseases. In East Asians, a loss-of-function variant in the PLA2G7 gene can be used to assess the effects of genetically determined lower Lp-PLA2 METHODS: PLA2G7 V279F (rs76863441) was genotyped in 91 428 individuals randomly selected from the China Kadoorie Biobank of 0.5 M participants recruited in 2004-08 from 10 regions of China, with 7 years' follow-up. Linear regression was used to assess effects of V279F on baseline traits. Logistic regression was conducted for a range of vascular and non-vascular diseases, including 41 ICD-10 coded disease categories. PLA2G7 V279F frequency was 5% overall (range 3-7% by region), and 9691 (11%) participants had at least one loss-of-function variant. V279F was not associated with baseline blood pressure, adiposity, blood glucose or lung function. V279F was not associated with major vascular events [7141 events; odds ratio (OR) = 0.98 per F variant, 95% confidence interval (CI) 0.90-1.06] or other vascular outcomes, including major coronary events (922 events; 0.96, 0.79-1.18) and stroke (5967 events; 1.00, 0.92-1.09). Individuals with V279F had lower risks of diabetes (7031 events; 0.91, 0.84-0.98) and asthma (182 events; 0.53, 0.28-0.98), but there was no association after adjustment for multiple testing. Lifelong lower Lp-PLA2 activity was not associated with major risks of vascular or non-vascular diseases in Chinese adults. Using functional genetic variants in large-scale prospective studies with linkage to a range of health outcomes is a valuable approach to inform drug development and repositioning.


Cerebrovascular pattern improved by ozone autohemotherapy: an entropy-based study on multiple sclerosis patients.
Ozone major autohemotherapy is effective in reducing the symptoms of multiple sclerosis (MS) patients, but its effects on brain are still not clear. In this work, we have monitored the changes in the cerebrovascular pattern of MS patients and normal subjects during major ozone autohemotherapy by using near-infrared spectroscopy (NIRS) as functional and vascular technique. NIRS signals are analyzed using a combination of time, time-frequency analysis and nonlinear analysis of intrinsic mode function signals obtained from empirical mode decomposition technique. Our results show that there is an improvement in the cerebrovascular pattern of all subjects indicated by increasing the entropy of the NIRS signals. Hence, we can conclude that the ozone therapy increases the brain metabolism and helps to recover from the lower activity levels which is predominant in MS patients.


Reliability of content-addressable data search in a defocused volume holographic data storage system.
We investigate for suitable methods that enable reliable content-addressable data search in a defocused volume holographic data storage system. Two techniques have been introduced and are shown to overcome the shortcomings of the known methods used to perform content searching in defocused holographic recording geometry. In effect, we remove the deterministic errors that result because of the presence of nonmatching database records, producing almost the same correlation scores as the true targeted correlation scores. Such deterministic errors give rise to erroneous search outcomes and reduce the speed advantage of the parallel holographic data search. We present experimental results and discuss the improvements offered by the two introduced methods in terms of storage density and measured correlation scores. Both the methods of modified-balanced and 25% sparse modulation coded data pages are found to produce good results, negating the undesired correlation characteristics.


Real-time adaptive planning method for radiotherapy treatment delivery for prostate cancer patients, based on a library of plans accounting for possible anatomy configuration changes.
In prostate cancer treatment with external beam radiation therapy (EBRT), prostate motion and internal changes in tissue distribution can lead to a decrease in plan quality. In most currently used planning methods, the uncertainties due to prostate motion are compensated by irradiating a larger treatment volume. However, this could cause underdosage of the treatment volume and overdosage of the organs at risk (OARs). To reduce this problem, in this proof of principle study we developed and evaluated a novel adaptive planning method. The strategy proposed corrects the dose delivered by each beam according to the actual position of the target in order to produce a final dose distribution dosimetrically as similar as possible to the prescribed one. Our adaptive planning method was tested on a phantom case and on a clinical case. For the first, a pilot study was performed on an in-silico pelvic phantom. A "library" of intensity modulated RT (IMRT) plans corresponding to possible positions of the prostate during a treatment fraction was generated at planning stage. Then a 3D random walk model was used to simulate possible displacements of the prostate during the treatment fraction. At treatment stage, at the end of each beam, based on the current position of the target, the beam from the library of plans, which could reproduce the best approximation of the prescribed dose distribution, was selected and delivered. In the clinical case, the same approach was used on two prostate cancer patients: for the first a tissue deformation was simulated in-silico and for the second a cone beam CT (CBCT) taken during the treatment was used to simulate an intra-fraction change. Then, dosimetric comparisons with the standard treatment plan and, for the second patient, also with an isocenter shift correction, were performed. For the phantom case, the plan generated using the adaptive planning method was able to meet all the dosimetric requirements and to correct for a misdosage of 13% of the dose prescription on the prostate. For the first clinical case, the standard planning method caused underdosage of the seminal vesicles, respectively by 5% and 4% of the prescribed dose, when the position changes for the target were correctly taken into account. The proposed adaptive planning method corrected any possible missed target coverage, reducing at the same time the dose on the OARs. For the second clinical case, both with the standard planning strategy and with the isocenter shift correction target coverage was significantly worsened (in particular uniformity) and some organs exceeded some toxicity objectives. While with our approach, the most uniform coverage for the target was produced and systematically the lowest toxicity values for the organs at risk were achieved. In our proof of principle study, the adaptive planning method performed better than the standard planning and the isocenter shift methods for prostate EBRT. It improved the coverage of the treatment volumes and lowered the dose to the OARs. This planning method is particularly promising for hypofractionated IMRT treatments in which a higher precision and control on dose deposition are needed. Further studies will be performed to test more extensively the proposed adaptive planning method and to evaluate it at a full clinical level.


Computerized simulation of color appearance for anomalous trichromats using the multispectral image.
Most color simulators for color deficiencies are based on the tristimulus values and are intended to simulate the appearance of an image for dichromats. Statistics show that there are more anomalous trichromats than dichromats. Furthermore, the spectral sensitivities of anomalous cones are different from those of normal cones. Clinically, the types of color defects are characterized through Rayleigh color matching, where the observer matches a spectral yellow to a mixture of spectral red and green. The midpoints of the red/green ratios deviate from a normal trichromat. This means that any simulation based on the tristimulus values defined by a normal trichromat cannot predict the color appearance of anomalous Rayleigh matches. We propose a computerized simulation of the color appearance for anomalous trichromats using multispectral images. First, we assume that anomalous trichromats possess a protanomalous (green shifted) or deuteranomalous (red shifted) pigment instead of a normal (L or M) one. Second, we assume that the luminance will be given by L+M, and red/green and yellow/blue opponent color stimulus values are defined through L-M and (L+M)-S, respectively. Third, equal-energy white will look white for all observers. The spectral sensitivities of the luminance and the two opponent color channels are multiplied by the spectral radiance of each pixel of a multispectral image to give the luminance and opponent color stimulus values of the entire image. In the next stage of color reproduction for normal observers, the luminance and two opponent color channels are transformed into XYZ tristimulus values and then transformed into sRGB to reproduce a final image for anomalous trichromats. The proposed simulation can be used to predict the Rayleigh color matches for anomalous trichromats. We also conducted experiments to evaluate the appearance of simulated images by color deficient observers and verified the reliability of the simulation.


A generalized linear model for estimating spectrotemporal receptive fields from responses to natural sounds.
In the auditory system, the stimulus-response properties of single neurons are often described in terms of the spectrotemporal receptive field (STRF), a linear kernel relating the spectrogram of the sound stimulus to the instantaneous firing rate of the neuron. Several algorithms have been used to estimate STRFs from responses to natural stimuli; these algorithms differ in their functional models, cost functions, and regularization methods. Here, we characterize the stimulus-response function of auditory neurons using a generalized linear model (GLM). In this model, each cell's input is described by: 1) a stimulus filter (STRF); and 2) a post-spike filter, which captures dependencies on the neuron's spiking history. The output of the model is given by a series of spike trains rather than instantaneous firing rate, allowing the prediction of spike train responses to novel stimuli. We fit the model by maximum penalized likelihood to the spiking activity of zebra finch auditory midbrain neurons in response to conspecific vocalizations (songs) and modulation limited (ml) noise. We compare this model to normalized reverse correlation (NRC), the traditional method for STRF estimation, in terms of predictive power and the basic tuning properties of the estimated STRFs. We find that a GLM with a sparse prior predicts novel responses to both stimulus classes significantly better than NRC. Importantly, we find that STRFs from the two models derived from the same responses can differ substantially and that GLM STRFs are more consistent between stimulus classes than NRC STRFs. These results suggest that a GLM with a sparse prior provides a more accurate characterization of spectrotemporal tuning than does the NRC method when responses to complex sounds are studied in these neurons.


International conference on physical activity and obesity in children: summary statement and recommendations.
The increasing prevalence of obesity among the world's children and youth was the impetus for an international conference convened in Toronto, Canada to examine issues related to physical activity and obesity in children (June 24-27, 2007). The goal of the conference was to assimilate, interpret and share scientific evidence with key stakeholders to develop recommendations concerning effective physical activity policies and programs to address obesity in children. The conference was attended by approximately 1000 delegates from 33 countries who gathered to listen to the invited speakers and to share information on promising practices related to the promotion of physical activity with the aim to reduce the burden of obesity in children. The major topics addressed at the conference included the biological and behavioural causes of obesity, current and past levels of physical activity and sedentarism in children, the role of the social, family and built environment in addressing the physical activity deficit, and the role of legislation and industry in promoting physical activity. Promising physical activity interventions among children were presented, and important research, policy and practice recommendations to address the issue of physical inactivity and obesity were provided.


Methods used by critical care nurses to verify feeding tube placement in clinical practice.
The American Association of Critical-Care Nurses practice alert on verification of feeding tube placement makes evidence-based practice recommendations to guide nursing management of adult patients with blindly inserted feeding tubes. Many bedside verification methods do not allow detection of improper positioning of a feeding tube within the gastrointestinal tract, thereby increasing aspiration risk. To determine how the expected practices from the American Association of Critical-Care Nurses practice alert were implemented by critical care nurses. This study was part of a larger national, online survey that was completed by 370 critical care nurses. Descriptive statistics were used to analyze the data. Seventy-eight percent of nurses used a variety of methods to verify initial placement of feeding tubes, although 14% were unaware that tube position should be confirmed every 4 hours. Despite the inaccuracy of auscultation methods, only 12% of nurses avoided this practice all of the time. Implementation of expected clinical practices from this guideline varied. Nurses are encouraged to implement expected practices from this evidence-based, peer reviewed practice alert to minimize risk for patient harm.


Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component.
New therapeutic approaches in Alzheimer's disease are urgently needed. The normal plasma protein, serum amyloid P component (SAP), is always present in cerebrospinal fluid (CSF) and in the pathognomonic lesions of Alzheimer's disease, cerebrovascular and intracerebral Abeta amyloid plaques and neurofibrillary tangles, as a result of its binding to amyloid fibrils and to paired helical filaments, respectively. SAP itself may also be directly neurocytotoxic. Here, in this unique study in Alzheimer's disease of the bis(d-proline) compound, (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC), we observed depletion of circulating SAP and also remarkable, almost complete, disappearance of SAP from the CSF. We demonstrate that SAP depletion in vivo is caused by CPHPC cross-linking pairs of SAP molecules in solution to form complexes that are immediately cleared from the plasma. We have also solved the structure of SAP complexed with phosphothreonine, its likely ligand on hyperphosphorylated tau protein. These results support further clinical study of SAP depletion in Alzheimer's disease and potentially other neurodegenerative diseases.