Public engagement workshop: how to improve medicines for older people?
Public engagement in medication management has become more and more important in promoting population health. A public engagement workshop attended by 78 members of the geriatric community, family carers as well as professionals from academic research, industry and regulatory agencies entitled 'How to improve medicines for older people?' took place on the 2nd July 2013 at the University College London (UCL) School of Pharmacy. The main aim of the event was to provide a dynamic environment for information exchange and to identify ways of improving current and future geriatric drug therapy. The day opened with presentations from UCL School of Pharmacy researchers on the use of medicines at home, formulations, administration devices and multi-component compliance aids (MCAs) whilst a representative from UCL Interaction Centre gave an insightful presentation on human errors and resilience strategies regarding medication use. These opening presentations encouraged participants to share their own experiences as well as initiating a lively debate. Following the plenary presentations, the workshop was divided into 8 groups for parallel discussion session. These opinion sharing sessions witnessed fruitful discussions between patients, carers and researchers. The day closed with a panel session of representatives from the European Medicines Agency (EMA), the Medicines and Healthcare products Regulatory Agency (MHRA), the Geriatric Medicines Society and Guy's and St. Thomas' NHS Foundation Trust (GSTT). Participants were encouraged to voice their questions, concerns and recommendations about medications. The main concern expressed by both patients and carers from the workshop were (but are not limited to) formulation changes, MCA accessibility difficulties, interactions of different medicines, carers' concerns with the administration of medicines and not having enough knowledge of services provided by community pharmacists i.e. medicines use reviews (MURs) or new medicine service (NMS). Overall, this workshop created a useful forum for members of the geriatric community, their carers as well as research and industrial professionals to have an input in the improvement and management of geriatric drug therapy and this event also provided an excellent opportunity for the researchers to share the latest research innovations with attendees.


Sitagliptin, a dipeptidyl peptidase-4 inhibitor, in patients with short bowel syndrome and colon in continuity: an open-label pilot study.
Patients with short bowel syndrome (SBS) and colon in continuity have better adaptation potential compared with patients with jejunostomy. Adaptation may involve enhanced postprandial secretion of the enteroendocrine hormones glucagon-like peptide (GLP)-1 and GLP-2 which are normally degraded by dipeptidyl peptidase (DPP)-4. Nevertheless, some patients with SBS with colon in continuity suffer from high-volume faecal excretions and have been shown to benefit from treatment with GLP-2. Therefore, we aimed to evaluate efficacy of sitagliptin, a DPP-4 inhibitor, on reducing faecal excretions in this patient group. In an open-label, case series, proof-of-concept pilot study, 100 mg oral sitagliptin was given two times per day for 8 weeks to patients with SBS with ≥50% colon in continuity with or without the need for parenteral support (PS). To assess intestinal function, metabolic balance studies were done at baseline and following 8 weeks of treatment. Of the 10 patients planned for enrolment, 8 patients were included; 7 patients completed the study. Although postprandial endogenous GLP-2 concentrations increased by 49 hours×pmol/L (39, 105; p=0.018) (median (min, max)), sitagliptin did not significantly reduce median faecal wet weight (-174 g/day (-1510, 675; p=0.176)) or increase intestinal wet weight absorption. However, heterogeneity in the treatment effect was observed: intestinal wet weight absorption increased in all four patients with intestinal failure. One patient achieved a reduction in PS by 500 mL per administration day. Following this negative, small pilot study, larger, placebo-controlled, studies are needed to establish the therapeutic potential of DPP-4 inhibition in patients with SBS.


Enhanced RGB-D Mapping Method for Detailed 3D Indoor and Outdoor Modeling.
RGB-D sensors (sensors with RGB camera and Depth camera) are novel sensing systems that capture RGB images along with pixel-wise depth information. Although they are widely used in various applications, RGB-D sensors have significant drawbacks including limited measurement ranges (e.g., within 3 m) and errors in depth measurement increase with distance from the sensor with respect to 3D dense mapping. In this paper, we present a novel approach to geometrically integrate the depth scene and RGB scene to enlarge the measurement distance of RGB-D sensors and enrich the details of model generated from depth images. First, precise calibration for RGB-D Sensors is introduced. In addition to the calibration of internal and external parameters for both, IR camera and RGB camera, the relative pose between RGB camera and IR camera is also calibrated. Second, to ensure poses accuracy of RGB images, a refined false features matches rejection method is introduced by combining the depth information and initial camera poses between frames of the RGB-D sensor. Then, a global optimization model is used to improve the accuracy of the camera pose, decreasing the inconsistencies between the depth frames in advance. In order to eliminate the geometric inconsistencies between RGB scene and depth scene, the scale ambiguity problem encountered during the pose estimation with RGB image sequences can be resolved by integrating the depth and visual information and a robust rigid-transformation recovery method is developed to register RGB scene to depth scene. The benefit of the proposed joint optimization method is firstly evaluated with the publicly available benchmark datasets collected with Kinect. Then, the proposed method is examined by tests with two sets of datasets collected in both outside and inside environments. The experimental results demonstrate the feasibility and robustness of the proposed method.


Herbivore exclusion promotes a more stochastic plant community assembly in a natural grassland.
Both bottom-up (e.g., nutrients) and top-down (e.g., herbivory) forces structure plant communities, but it remains unclear how they affect the relative importance of stochastic and deterministic processes in plant community assembly. Moreover, different-sized herbivores have been shown to have contrasting effects on community structure and function, but their effects on the processes governing community assembly (i.e., how they generate the impacts on structure) remain largely unknown. We evaluated the influence of bottom-up and top-down forces on the relative importance of deterministic and stochastic processes during plant community assembly. We used the data of a 7-yr factorial experiment manipulating nutrient availability (ambient and increased) and the presence of vertebrate herbivores (>1 kg) of different body size in a floodplain grassland in The Netherlands. We used a null model that describes a community composition expected by chance (i.e., stochastic assembly) and compared the plant community composition in the different treatments with this null model (the larger the difference, the more deterministically assembled). Our results showed that herbivore exclusion promoted a more stochastic plant community assembly, whereas increased nutrients played a relatively minor role in determining the relative importance of stochasticity in community assembly. Large herbivores facilitated intermediate-sized mammal herbivores, resulting in synergistic effects of enhanced grazing pressure and a more deterministic and convergent plant community assembly. We conclude that herbivores can act as strong deterministic forces during community assembly in natural systems. Our results also reveal that although large- and intermediate-sized mammal herbivores often have contrasting effects on many community and ecosystem properties, they can also synergistically homogenize plant communities.


Time-dependently expressed markers and the characterization for premature senescence induced by ionizing radiation in MCF7.
Senescence has been suggested as a defense mechanism to block sporadic induction of cancer cells. Radiation treatment induces proliferating cancer cells to turn into non-proliferating senescent cells in vitro. To characterize transcriptional reprogramming after radiation treatment, we measured the gene expression profiles of MCF7 at different time points after treatment. In these experiments, we found that IR induced premature senescence in MCF7 cells, and IR treatment resulted in significant changes in the expression of 305 marker genes (<1% FDR), which were strongly correlated (|r|>0.9) with IR treatment in a time-dependent manner. Functional analysis of these markers indicated that the dynamics of cytoskeletal structure and lysosomal activity gradually increased. The expression of maker genes for modulator proteins, that were responsible for the dynamics of actin stress fibers and focal adhesion, displayed a particularly strong positive correlation with senescence-associated (SA) morphological changes through time. We also observed a strong induction of genes related to lysosomal metabolic activity, which was accompanied by an increase in the number of SA-beta-Gal positive cells. However, the expression of genes for cell cycle progression, post-transcription and translation activities gradually decreased after radiation treatment. Especially, we observed clear cell cycle arrest specifically at the S and G2/M phases with consistent down-regulation of genes for microtubule assembly/disassembly or spindle biogenesis.


Australian football player work rate: evidence of fatigue and pacing?
Previous research has suggested elite Australian footballers undertake pacing strategies to preserve high intensity activity later in matches. However, this research used GPS with slow sample rates, did not express performance relative to minutes played during games and used lowly ranked players. Therefore in this study movement was recorded by GPS at 5 Hz. Running performance was expressed per period of the match (rotation) divided into low-intensity activity (LIA, 0.10 to 4.17 m x s(-1)); high-intensity running (HIR, 4.17 to 10.00 m x s(-1)) and maximal accelerations (2.78 to 10.00 m x s(-2)). All data were expressed relative to the first period of play in the match and the magnitude of effects was analyzed with the effect size (ES) statistic and expressed with confidence intervals. The total and LIA distance covered by players did not change by a practically important magnitude during games (ES< 0.20). High intensity running was reduced in both rotations of the second quarter, Q3R2 and both rotations of the fourth quarter (ES -0.30 ± 0.14; -0.42 ± 0.14; -0.30 ± 0.14; -0.42 ± 0.14; and -0.48 ± 0.15 respectively). Maximal acceleration performance was reduced in Q1R2, and each rotation of the second half of matches. When expressed per minute of game time played, total distance and low intensity activity distance are not reduced by a practically important magnitude in AF players during a match. These data are therefore inconsistent with the concept of team sport players pacing their effort during matches. However, both high intensity running and maximal accelerations are reduced later in games, indicative of significant fatigue in players.


Glycerol monolaurate inhibits Candida and Gardnerella vaginalis in vitro and in vivo but not Lactobacillus.
We investigated the effects of glycerol monolaurate (GML) on Lactobacillus, Candida, and Gardnerella vaginalis human vaginal microflora. Our previous work demonstrated that 6 months of GML treatment vaginally does not alter lactobacillus counts in monkeys. Candida and G. vaginalis are commonly associated with vaginal infections in women, many becoming chronic or recurrent. In vitro growth inhibition studies determined the effects of GML (0 to 500 microg/ml) against multiple Candida species and G. vaginalis. A randomized, double-blind study investigated the effects of GML on vaginal microflora Lactobacillus, Candida, and G. vaginalis in colonized or infected women (n=36). Women self-administered intravaginal gels containing 0% (n=14), 0.5% (n=13), or 5% (n=9) GML every 12 h for 2 days. Vaginal swabs were collected before and immediately after the first gel administration and 12 h after the final gel administration. Swabs were tested for Lactobacillus, Candida, G. vaginalis, and GML. In vitro GML concentrations of 500 microg/ml were candicidal for all species tested, while a concentration of 10 microg/ml was bactericidal for G. vaginalis. Control and GML gels applied vaginally in women did not alter vaginal pH or Lactobacillus counts. Control gels reduced G. vaginalis counts but not Candida counts, whereas GML gels reduced both Candida and G. vaginalis. No adverse events were reported by participating women. GML is antimicrobial for Candida and G. vaginalis in vitro. Vaginal GML gels in women do not affect Lactobacillus negatively but significantly reduce Candida and G. vaginalis.


Surface-Enhanced Raman Spectroscopy for Identification of Heavy Metal Arsenic(V)-Mediated Enhancing Effect on Antibiotic Resistance.
Bacterial antibiotic resistance poses a threat to global public health. Restricted usage of antibiotics does not necessarily prevent its continued emergence. Rapid and sensitive screening of triggers, in addition to antibiotic, and exploring the underlying mechanism are still major challenges. Herein, by developing a homogeneous vacuum filtration-based bacterial sample fabrication enabling high surface-enhanced Raman scattering (SERS) reproducibility across multiple bacterial samples and negating interfering spectral variations from inhomogeneous sample geometry and SERS enhancement, SERS was employed to study heavy metal arsenic [As(V)]-mediated antibiotic resistance in a robust, sensitive, and rapid fashion. Independent and robust spectral changes representing phenotypic bacterial responses, combined with multivariate analysis, clearly identified that As(V) enhanced antibiotic resistance to tetracycline (Tet). Similar spectral alteration profile to As(V) and Tet indicated that cross-resistance, whereby As(V)-induced bacterial resistance simultaneously blocked Tet action, could account for the enhanced resistance. The sensitive, robust, and rich phenotypic profile provided by SERS, combined with additional advantages in imposing no need to cultivate bacteria and single-cell sensitivity, can be further exploited to evaluate resistance-intervening factors in real microbiota.


Neuronally released norepinephrine does not preferentially activate postjunctional alpha 1-adrenoceptors in human blood vessels in vitro.
Human isolated digital arteries and metatarsal veins, obtained postmortem, have been used to compare the effects of alpha-adrenoceptor antagonists on contractile responses to nerve stimulation. The antagonists used were prazosin, rauwolscine, BE 2254, and yohimbine. Rauwolscine (alpha 2-antagonist), as well as prazosin and BE 2254 (alpha 1-antagonists), in concentrations of 10(-9), 10(-8), and 10(-7) mol/liter, potently antagonized the frequency-response curves to nerve stimulation. Yohimbine (alpha 2-antagonist) was slightly less potent, failing to antagonize responses to nerve stimulation in arteries at the concentration of 10(-9) mol/liter significantly, but producing potent antagonism of responses in both arteries and veins at higher concentrations (10(-8), 10(-7) mol/liter). All antagonists inhibited the contractile responses to nerve stimulation to a greater extent in veins than in arteries. Rauwolscine (10(-9), 10(-8), and 10(-7) mol/liter) and BE 2254 (10(-7) but not 10(-8) mol/liter) significantly enhanced stimulation-induced tritium efflux in arteries and veins. These results suggest that alpha 2-adrenoceptor antagonists, despite their prejunctional effects, are potent antagonists of contractile responses to nerve stimulation. Thus, in these human blood vessels, endogenously released norepinephrine does not preferentially activate postjunctional alpha 1-adrenoceptors, but activates receptors with the properties of both the alpha 1- and alpha 2-adrenoceptor subtypes.


Household costs and time to treatment for children with severe febrile illness in rural Burkina Faso: the role of rectal artesunate.
Community health workers (CHWs) were trained to identify children with malaria who could not take oral medication, treat them with rectal artesunate (RA) and refer them to the closest healthcare facility to complete management. However, many children with such symptoms did not seek CHWs' care. The hypothesis was that the cost of referral to a health facility was a deterrent. The goal of this study was to compare the out-of-pocket costs and time to seek treatment for children who sought CHW care (and received RA) versus those who did not. Children with symptoms of severe malaria receiving RA at CHWs and children with comparable disease symptoms who did not go to a CHW were identified and their parents were interviewed. Household out-of-pocket costs per illness episode and speed of treatment were evaluated and compared between RA-treated children vs. non-RA treated children and by central nervous symptoms (CNS: repeated convulsions, altered consciousness or coma). Among children with CNS symptoms, costs of RA-treated children were similar to those of non-RA treated children ($5.83 vs. $4.65; p = 0.52), despite higher transport costs ($2.74 vs. $0.91; p < 0.0001). However, among children without CNS symptoms, costs of RA-treated children were higher than the costs of non-RA treated children with similar symptoms ($5.62 vs. $2.59; p = 0.0001), and the main driver of the cost difference was transport. After illness onset, CNS children reached CHWs for RA an average of 9.0 h vs. 16.1 h for non-RA treated children reaching first treatment [difference 7.1 h (95% CI - 1.8 to 16.1), p = 0.11]. For non-CNS patients the average time to CHW-delivered RA treatment was 12.2 h vs. 20.1 h for those reaching first treatment [difference 7.9 h (95% CI 0.2-15.6), p = 0.04]. More non-RA treated children developed CNS symptoms before arrival at the health centre but the difference was not statistically significant (6% vs. 4%; p = 0.58). Community health worker-delivered RA does not affect the total out-of-pocket costs when used in children with CNS symptoms, but is associated with higher total out-of-pocket costs when used in children with less severe symptoms. RA-treated children sought treatment more quickly.


I feel who I see: visual body identity affects visual-tactile integration in peripersonal space.
Recent studies have shown the importance of integrating multisensory information in the body representation for constituting self-consciousness. However, one idea that has received only scant attention is that our body representation is also constituted by knowledge of bodily visual characteristics (i.e. 'what I look like'). Here in two experiments we used a full body crossmodal congruency task in which visual distractors were presented on a photograph of the participant, another person, who was either familiar or unfamiliar, or an object. Results revealed that during the 'self-condition' CCEs were enhanced compared to the 'other condition'. The CCE was similar for unfamiliar and familiar others. CCEs for the object condition were significantly smaller. The results show that presentation of an irrelevant image of a body affects multimodal processing and that the effect is enhanced when that image is of the self. The results hold intriguing implications for body representation in social situations.


Confidence and central tendency in perceptual judgment.
This paper theoretically and empirically investigates the role of noisy cognition in perceptual judgment, focusing on the central tendency effect: the well-known empirical regularity that perceptual judgments are biased towards the center of the stimulus distribution. Based on a formal Bayesian framework, we generate predictions about the relationships between subjective confidence, central tendency, and response variability. Specifically, our model clarifies that lower subjective confidence as a measure of posterior uncertainty about a judgment should predict (i) a lower sensitivity of magnitude estimates to objective stimuli; (ii) a higher sensitivity to the mean of the stimulus distribution; (iii) a stronger central tendency effect at higher stimulus magnitudes; and (iv) higher response variability. To test these predictions, we collect a large-scale experimental data set and additionally re-analyze perceptual judgment data from several previous experiments. Across data sets, subjective confidence is strongly predictive of the central tendency effect and response variability, both correlationally and when we exogenously manipulate the magnitude of sensory noise. Our results are consistent with (but not necessarily uniquely explained by) Bayesian models of confidence and the central tendency.


Thermal effects on electronic properties of CO/Pt(111) in water.
Structure and adsorption energy of carbon monoxide molecules adsorbed on the Pt(111) surfaces with various CO coverages in water as well as work function of the whole systems at room temperature of 298 K were studied by means of a hybrid method that combines classical molecular dynamics and density functional theory. We found that when the coverage of CO is around half monolayer, i.e. 50%, there is no obvious peak of the oxygen density profile appearing in the first water layer. This result reveals that, in this case, the external force applied to water molecules from the CO/Pt(111) surface almost vanishes as a result of the competitive adsorption between CO and water molecules on the Pt(111) surface. This coverage is also the critical point of the wetting/non-wetting conditions for the CO/Pt(111) surface. Averaged work function and adsorption energy from current simulations are consistent with those of previous studies, which show that thermal average is required for direct comparisons between theoretical predictions and experimental measurements. Meanwhile, the statistical behaviors of work function and adsorption energy at room temperature have also been calculated. The standard errors of the calculated work function for the water-CO/Pt(111) interfaces are around 0.6 eV at all CO coverages, while the standard error decreases from 1.29 to 0.05 eV as the CO coverage increases from 4% to 100% for the calculated adsorption energy. Moreover, the critical points for these electronic properties are the same as those for the wetting/non-wetting conditions. These findings provide a better understanding about the interfacial structure under specific adsorption conditions, which can have important applications on the structure of electric double layers and therefore offer a useful perspective for the design of the electrochemical catalysts.


The Tumor Metabolic Microenvironment: Lessons from Lactate.
The extracellular milieu of tumors is generally assumed to be immunosuppressive due in part to metabolic factors. Here, we review methods for probing the tumor metabolic microenvironment. In parallel, we consider the resulting available evidence, with a focus on lactate, which is the most strongly increased metabolite in bulk tumors. Limited microenvironment concentration measurements suggest depletion of glucose and modest accumulation of lactate (less than 2-fold). Isotope tracer measurements show rapid lactate exchange between the tumor and circulation. Such exchange is catalyzed by MCT transporters, which cotransport lactate and protons (H+). Rapid lactate exchange seems at odds with tumor lactate accumulation. We propose a potential resolution to this paradox. Because of the high pH of tumor cells relative to the microenvironment, H+-coupled transport by MCTs tends to drive lactate from the interstitium into tumor cells. Accordingly, lactate may accumulate preferentially in tumor cells, not the microenvironment. Thus, although they are likely subject to other immunosuppressive metabolic factors, tumor immune cells may not experience a high lactate environment. The lack of clarity regarding microenvironmental lactate highlights the general need for careful metabolite measurements in the tumor extracellular milieu.


The effect of quadriceps muscle fatigue on position matching at the knee.
This is a report of the effects of exercise on position matching at the knee. Young adult subjects were required to step down a set of stairs (792 steps), representing eccentric-biased exercise of the quadriceps muscle, or step up them, concentric-biased exercise. Immediately after eccentric exercise subjects showed a mean force drop of 28% (+/- 6%, s.e.m.) of the control value in their exercised quadriceps muscle, which was accompanied by 4.8 deg (+/- 0.8 deg) of error between reference and matching legs in a position matching task at the knee. Similarly concentric exercise was followed by a force drop of 15% (+/- 3%) and matching errors of 3.7 deg (+/- 0.4 deg). These effects were significant. The direction of the errors suggested that subjects perceived their exercised muscles to be longer that they actually were. This finding was not consistent with the hypothesis that the increase in effort required to support the leg after fatigue from exercise was responsible for the errors. It is hypothesized that position sense in an unsupported leg arises, in part, from operation of an internal forward model. When the motor command is increased to compensate for the effects of fatigue, the comparison between predicted and actual feedback from quadriceps leads to the impression that the muscle is longer than it actually is. The exercise effects on proprioception may have implications for sports injuries and for evaluation of the factors leading to falls in the elderly.


Hydrogen peroxide concentration by pervaporation of a ternary liquid solution in microfluidics.
Pervaporation in a microfluidic device is performed on liquid ternary solutions of hydrogen peroxide-water-methanol in order to concentrate hydrogen peroxide (H2O2) by removing methanol. The quantitative analysis of the pervaporation of solutions with different initial compositions is performed, varying the operating temperature of the microfluidic device. Experimental results together with a mathematical model of the separation process are used to understand the effect of the operating conditions on the microfluidic device efficiency. The parameters influencing significantly the performance of pervaporation in the microfluidic device are determined and the limitations of the process are discussed. For the analysed system, the operating temperature of the chip has to be below the temperature at which H2O2 decomposes. Therefore, the choice of an adequate reduced operating pressure is required, depending on the expected separation efficiency.


Energy requirements during pregnancy and lactation.
To estimate the energy requirements of pregnant and lactating women consistent with optimal pregnancy outcome and adequate milk production. Total energy cost of pregnancy was estimated using the factorial approach from pregnancy-induced increments in basal metabolic rate measured by respiratory calorimetry or from increments in total energy expenditure measured by the doubly labelled water method, plus energy deposition attributed to protein and fat accretion during pregnancy. Database on changes in basal metabolic rate and total energy expenditure during pregnancy, and increments in protein based on measurements of total body potassium, and fat derived from multi-compartment body composition models was compiled. Energy requirements during lactation were derived from rates of milk production, energy density of human milk, and energy mobilisation from tissues. Healthy pregnant and lactating women. The estimated total cost of pregnancy for women with a mean gestational weight gain of 12.0 kg, was 321 or 325 MJ, distributed as 375, 1200, 1950 kJ day(-1), for the first, second and third trimesters, respectively. For exclusive breastfeeding, the energy cost of lactation was 2.62 MJ day(-1) based on a mean milk production of 749 g day(-1), energy density of milk of 2.8 kJ g(-1), and energetic efficiency of 0.80. In well-nourished women, this may be subsidised by energy mobilisation from tissues on the order of 0.72 MJ day(-1), resulting in a net increment of 1.9 MJ day(-1) over non-pregnant, non-lactating energy requirements. Recommendations for energy intake of pregnant and lactating women should be updated based on recently available data.


Advancing Competency-Based Medical Education: A Charter for Clinician-Educators.
The International Competency-Based Medical Education (ICBME) Collaborators have been working since 2009 to promote understanding of competency-based medical education (CBME) and accelerate its uptake worldwide. This article presents a charter, supported by a literature-based rationale, which is meant to provide a shared mental model of CBME that will serve as a path forward in its widespread implementation.At a 2013 summit, the ICBME Collaborators laid the groundwork for this charter. Here, the fundamental principles of CBME and professional responsibilities of medical educators in its implementation process are described. The authors outline three fundamental principles: (1) Medical education must be based on the health needs of the populations served; (2) the primary focus of education and training should be the desired outcomes for learners rather than the structure and process of the educational system; and (3) the formation of a physician should be seamless across the continuum of education, training, and practice.Building on these principles, medical educators must demonstrate commitment to teaching, assessing, and role modeling the range of identified competencies. In the clinical setting, they must provide supervision that balances patient safety with the professional development of learners, being transparent with stakeholders about level of supervision needed. They must use effective and efficient assessment strategies and tools for basing transition decisions on competence rather than time in training, empowering learners to be active participants in their learning and assessment. Finally, advancing CBME requires program evaluation and research, faculty development, and a collaborative approach to realize its full potential.


Long-term outcome and tolerability of the ketogenic diet in drug-resistant childhood epilepsy--the Austrian experience.
To evaluate the long-term efficacy/tolerability of the ketogenic diet (KD) in paediatric drug-resistant epilepsies. Data from children who were treated between 1999 and 2008 and had continuous follow-up of at least 6 months after initiation of the KD were analysed retrospectively. Response was defined as > or = 50% seizure reduction. Treatment effects on EEG, developmental outcome and the "outcome-predictive" value of various clinical factors were also assessed. 50 children (22 boys; mean age 4.5 years+/-3.55) were included. Mean follow-up was 3.93+/-2.95. 50% of the patients were responders, 48% of them became seizure free. 50% were non-responders, 20% of them deteriorated. In responders, EEG background activity improved significantly (p=0.014) and a significantly lower rate of epileptic discharges (p=0.009) was seen after 6 months. In addition, neurological examination findings demonstrated significant developmental progress (p=0.038). Favourable treatment outcome was associated with a shorter disease duration (p=0.025) and generalised tonic clonic seizures (p=0.059). No further significant outcome predictors were detected. However, response was 44% in patients with infantile spasms, 62.5% in those with Dravet syndrome and 50% in Lennox-Gastaut-syndrome. Side effects occurred in 28%, but discontinuation of the KD was not required in any case. They most often observed with concomitant topiramate (p=0.001) and valproate (p=0.046). Despite the retrospective nature of the study and the inhomogeneous patient sample, we found good long-term effects of the KD on seizure frequency, EEG and neurological development.


Mechanisms of skin tanning in different racial/ethnic groups in response to ultraviolet radiation.
Ultraviolet radiation stimulates pigmentation in human skin, but the mechanism(s) whereby this increase in melanin production (commonly known as tanning) occurs is not well understood. Few studies have examined the molecular consequences of UV on human skin of various racial backgrounds in situ. We investigated the effects of UV on human skin of various races before and at different times after a single 1 minimal erythemal dose UV exposure. We measured the distribution of DNA damage that results, as well as the melanin content/distribution and the expression of various melanocyte-specific genes. The density of melanocytes at the epidermal:dermal junction in different types of human skin are remarkably similar and do not change significantly within 1 wk after UV exposure. The expression of melanocyte-specific proteins (including TYR (tyrosinase), TYRP1 (tyrosinase-related protein 1), DCT (tyrosinase-related protein 2), MART1 (melanoma antigens recognized by T-cells) gp100 (Pmel17/silver), and MITF (micropthalmia transcription factor)) increased from 0 to 7 d after UV exposure, but the melanin content of the skin increased only slightly. The most significant change, however, was a change in the distribution of melanin from the lower layer upwards to the middle layer of the skin, which was more dramatic in the darker skin. These results provide a basis for understanding the origin of different skin colors and responses to UV within different races.


Video traffic characteristics of modern encoding standards: H.264/AVC with SVC and MVC extensions and H.265/HEVC.
Video encoding for multimedia services over communication networks has significantly advanced in recent years with the development of the highly efficient and flexible H.264/AVC video coding standard and its SVC extension. The emerging H.265/HEVC video coding standard as well as 3D video coding further advance video coding for multimedia communications. This paper first gives an overview of these new video coding standards and then examines their implications for multimedia communications by studying the traffic characteristics of long videos encoded with the new coding standards. We review video coding advances from MPEG-2 and MPEG-4 Part 2 to H.264/AVC and its SVC and MVC extensions as well as H.265/HEVC. For single-layer (nonscalable) video, we compare H.265/HEVC and H.264/AVC in terms of video traffic and statistical multiplexing characteristics. Our study is the first to examine the H.265/HEVC traffic variability for long videos. We also illustrate the video traffic characteristics and statistical multiplexing of scalable video encoded with the SVC extension of H.264/AVC as well as 3D video encoded with the MVC extension of H.264/AVC.


Regulations, policies, and guidelines addressing environmental exposures in early learning environments: a review.
Infants and young children under five years of age are uniquely vulnerable to certain environmental contaminants. Some of these contaminants have been found in early learning environments (ELEs), or child care and family child care settings where children spend an average of 40 hours a week. These contaminants as well as infants' and children's unique physiology, exposures, and behaviors in child care settings are the focus of this article. Current child care and family child care licensing requirements specific to environmental health-related issues are also reviewed. Data were reviewed and analyzed from the following surveys: the 2008 Child Care Licensing Survey, the First National Environmental Health Survey of Child Care Centers, and the Children's Total Exposure to Persistent Pesticides and Other Persistent Organic Pollutants. The authors' analysis suggests that current state licensing programs impose only the most basic environmental health protection requirements. No mandatory federal regulations standardize child care and family child care regulatory efforts nationally. Resources are available, however, from federal agencies and other children's environmental health organizations that may provide guidance for how to establish better environmental health protection measures in ELEs.


Part 3. Assessment of genotoxicity and oxidative stress after exposure to diesel exhaust from U.S. 2007-compliant diesel engines: report on 1- and 3-month exposures in the ACES bioassay.
Human health hazards due to diesel exhaust (DE*) exposure have been associated with both solvent and combustion components. In the past, diesel engine exhaust components have been linked to increased mutagenicity in cultures of Salmonella typhimurium and mammalian cells (Tokiwa and Ohnishi 1986). In addition, DE has been shown to increase both the incidence of tumors and the induction of 8-hydroxy-deoxyguanosine adducts (8-OHdG) in ICR mice (Ichinose et al. 1997). Furthermore, DE is composed of a complex mixture of polycyclic aromatic hydrocarbons (PAHs) and particulates. One such PAH, 3-nitrobenzanthrone (3-NBA), has been identified in DE and found in urban air. 3-NBA has been observed to induce micronucleus formation in DNA of human hepatoma cells (Lamy et al. 2004). The purpose of the current research, which is part of the Advanced Collaborative Emissions Study (ACES), a multidisciplinary program being carried out by the Health Effects Institute and the Coordinating Research Council, is to determine whether improvements in the engineering of heavy-duty diesel engines reduce the oxidative stress and genotoxic risk associated with exposure to DE components. To this end, the genotoxicity and oxidative stress of DE from an improved diesel engine was evaluated in bioassays of tissues from Wistar Han rats and C57BL/6 mice exposed to DE. Genotoxicity was measured as strand breaks using an alkaline-modified comet assay. To correlate possible DNA damage found by the comet assay, measurement of DNA-adduct formation was evaluated by a competitive enzyme-linked immunosorbent assay (ELISA) to determine the levels of free 8-OHdG found in the serum of the animals exposed to DE. 8-OHdG is a specific modified base indicating an oxidative type of DNA damage to DNA nucleotides. In addition, a thiobarbituric acid reactive substances (TBARS) assay was used to assess oxidative stress and damage in the form of lipid peroxidation in the hippocampus region of the brains of DE-exposed animals. Results from the comet assay showed no significant differences in rats between the control and exposed groups (P = 0.53, low exposure; P = 0.92, medium exposure; P = 0.77, high exposure) after 1 month of DE exposure. There were no differences between sexes in the responses of rats to these exposures. Likewise, there were no significant differences found after 3 months of exposure. Similarly, no significant differences were found between the mice exposed for 1 and 3 months to DE, nor were any differences found between sexes. Measurements of 8-OHdG in both mice and rats showed no significant difference among DE exposure groups (P = 0.46, mice; P = 0.86, rats). In mice, measured 8-OHdG was lower in the 3-month group than the 1-month group. In rats, the inverse was true. In mice, no significant differences in the levels of lipid peroxidation, as measured by TBARS, were found between the controls and DE exposure groups (P = 0.92), nor were there any differences between sexes. In rats, comparisons between the control and low-exposure groups approached significance, but no significant differences were found between the other DE exposure groups. Additionally, in rats, there were no significant differences between the 1- and 3-month DE exposure groups.


Early- vs late-onset subcortical vascular cognitive impairment.
To evaluate the differences between early-onset subcortical vascular cognitive impairment (EO-SVCI) and late-onset subcortical vascular cognitive impairment (LO-SVCI) with regard to pathologic burden, structural changes, and cognitive function. We prospectively recruited 142 patients from a single referral center. Patients were divided into EO-SVCI (n = 30, age at onset <65 years) and LO-SVCI (n = 112, age at onset ≥ 65 years) groups. All patients underwent neuropsychological tests, 3T brain MRI, and [(11)C] Pittsburgh compound B (PiB)-PET. We compared pathologic burden such as small vessel disease and amyloid burden; structural changes such as structural network, cortical thickness, and hippocampal volume; and cognitive function between EO-SVCI and LO-SVCI. EO-SVCI patients had more lacunes, while LO-SVCI patients had higher PiB standardized uptake value ratios. EO-SVCI patients exhibited more severe structural network disruptions in the frontal area, while LO-SVCI patients exhibited more severe cortical and hippocampal atrophy. Although disease severity did not differ between the 2 groups, frontal-executive dysfunction was more severe in EO-SVCI patients. EO-SVCI patients showed more vascular related factors, while LO-SVCI patients exhibited more Alzheimer disease-related characteristics. The greater number of lacunes in EO-SVCI might account for the more severe frontal network disruption and frontal-executive dysfunction, while the greater amyloid burden in LO-SVCI might account for the more severe cortical and hippocampal atrophy. Our findings suggest that the age at onset is a crucial factor that determines distinct features in SVCI patients, such as pathologic burden, structural changes, and cognitive function.


Malaria transmission in Dakar: a two-year survey.
According to entomological studies conducted over the past 30 years, there was low malaria transmission in suburb of Dakar but little evidence of it in the downtown area. However; there was some evidence of local transmission based on reports of malaria among permanent residents. An entomological evaluation of malaria transmission was conducted from May 2005 to October 2006 in two areas of Dakar. Mosquitoes were sampled by human landing collection during 34 nights in seven places in Bel-air area (238 person-nights) and during 24 nights in five places in Ouakam area (120 person-nights). Mosquitoes were identified morphologically and by molecular methods. The Plasmodium falciparum circumsporozoïte indexes were measured by ELISA, and the entomological inoculation rates (EIR) were calculated for both areas. Molecular assessments of pyrethroid knock down resistance (Kdr) and of insensitive acetylcholinesterase resistance were conducted. From May 2005 to October 2006, 4,117 and 797 Anopheles gambiae s.l. respectively were caught in Bel-air and Ouakam. Three members of the complex were present: Anopheles arabiensis (> 98%), Anopheles melas (< 1%) and An. gambiae s.s. molecular form M (< 1%). Infected mosquitoes were caught only during the wintering period between September and November in both places. In 2005 and 2006, annual EIRs were 9,5 and 4, respectively, in Bel-air and 3 and 3, respectively, in Ouakam. The proportion of host-seeking An. gambiae s.l. captured indoors were 17% and 51% in Bel air and Ouakam, respectively. Ace 1 mutations were not identified in both members of the An. gambiae complex. Kdr mutation frequency in An. arabiensis was 12% in Bel-air and 9% in Ouakam. Malaria is transmitted in Dakar downtown area. Infected mosquitoes were caught in two subsequent years during the wintering period in two distant quarters of Dakar. These data agree with clinical data from a Senegalese military Hospital of Dakar (Hospital Principal) where most malaria cases occurred between October and December. It was the first detection of An. melas in Dakar.


PHYSICAL ACTIVITY, QUALITY OF LIFE AND BODY IMAGE OF CANDIDATES TO BARIATRIC SURGERY.
Physical activity enhances quality of life and body image in obese. Behavioural changes are useful tools to increase life conditions of this population. To evaluate the physical activity level of candidates to bariatric surgery and its relation with quality of life and body image, when patients are encouraged weekly by personal trainers. ) Method: This is a prospective, interventional and longitudinal study with quantitative analysis. Patients were divided into two groups, control (n=28) and interventional (n= 10). Both groups received physical activity and nutritional recommendations and psychological support. Were used the SF36 and Body Shape questionnaires to assess physical activity level and body image and pedometers to count weekly steps. Patients were followed during 12 weeks. ) Results: Were found significant difference in the domains physical activity (p=0.019), pain (p=0.0001) and health general status (p=0.021). No significant difference in body weight (p=0.095) was noted. When assisted by personal trainers, obese patients can change behavior, increase health quality and physical activity levels and experience less pain. Increase in physical activity, when well structured can benefit these patients.


Competitive adsorption of fibronectin and albumin on hydroxyapatite nanocrystals.
Competitive adsorption of two-component solutions containing fibronectin (Fn) and albumin (Ab) on hydroxyapatite (HAp) nanocrystals was analyzed in situ using the quartz crystal microbalance with dissipation (QCM-D) technique. Adsorption of the one-component protein (Fn or Ab) and the two-component proteins adjusted to different molar ratios of Fn to Ab at a fixed Fn concentration was investigated. The frequency shift (Δf; Hz) and the dissipation energy shift (ΔD) were measured with the QCM-D technique, and the viscoelastic changes of adlayers were evaluated by the saturated ΔD/Δf value and the Voigt-based viscoelastic model. For the adsorption of the one-component protein, the Fn adlayer showed a larger mass and higher viscoelasticity than the Ab adlayer, indicating the higher affinity of Fn on HAp. For the adsorption of the two-component proteins, the viscoelastic properties of the adlayers became elastic with increase in Ab concentration, whereas the adsorption mass was similar to that of Fn in the one-component solution regardless of the Ab concentration. The specific binding mass of the Ab antibody to the adlayers increased with increase in Ab concentration, whereas that of the Fn antibody decreased. Therefore, Fn preferentially adsorbs on HAp and Ab subsequently interacts with the adlayers, indicating that the interfacial viscoelasticity of the adlayers was dominated by the interaction between Fn and Ab.


Use of white blood cell growth factors and risk of acute myeloid leukemia or myelodysplastic syndrome among elderly patients with non-Hodgkin lymphoma.
The current study was conducted to evaluate the association between colony-stimulating factor (CSF) use and the risk of developing therapy-related myelodysplastic syndromes or acute myeloid leukemia (t-MDS/AML) among a large cohort of elderly patients with non-Hodgkin lymphoma (NHL) who were treated with chemotherapy. A total of 13,203 NHL patients were identified from the Surveillance, Epidemiology, and End Results-Medicare database who were diagnosed from 1992 through 2002. Patients were followed from their initial chemotherapy date until the date they were diagnosed with t-MDS/AML, death, or last follow-up (October 31, 2006), whichever occurred first. Overall, 40% (n = 5266) of patients received CSF. During the follow-up period (median follow-up, 2.9 years [range, 1-14.7 years]), 272 (5.2%) patients who were treated with CSF developed t-MDS/AML, compared with 230 (2.9%) patients who did not (P < .0001, log-rank test). The 5-year incidence of t-MDS/AML for patients receiving CSF was 14.1 per 1000 person-years compared with 8.3 per 1000 person-years for patients not receiving CSF. In a multivariable Cox regression analysis adjusted for gender, histology, stage, comorbidities, radiotherapy, and chemotherapy agent, CSF use was found to be independently associated with a 53% increased risk of t-MDS/AML (hazard ratio [HR], 1.53; 95% confidence interval [95% CI], 1.26-1.84). The observed association between CSF use and t-MDS/AML persisted across histologic subgroups (ie, diffuse large B-cell lymphoma, follicular lymphoma, and others). Patients who received both CSF and antimetabolite chemotherapy were found to have a 2.5-fold increased risk of t-MDS/AML (HR, 2.49; 95% CI, 1.91-3.26) compared with patients who received neither agent. The current study, which to our knowledge is the first large population-based study published to date, demonstrated that the administration of CSF among elderly NHL patients receiving chemotherapy was associated with an increased risk of t-MDS/AML, although the absolute risk was low.


Risk factors for healthcare-associated infection in pediatric intensive care units: a systematic review.
A systematic review of observational studies on risk factors for healthcare-associated infection in pediatric Intensive Care Units (ICU) was carried out. Studies indexed in MEDLINE, LILACS, Cochrane, BDENF, CAPES databases published in English, French, Spanish or Portuguese between 1987 and 2006 were included and cross references added. Key words for search were 'cross infection' and 'Pediatric Intensive Care Units' with others sub-terms included. 11 studies were selected from 419 originally found: four studies had healthcare-associated infection as the main outcome without a specific site; three articles identified factors associated with lower respiratory tract infection (pneumonia or tracheitis); three articles were concerned with laboratory-confirmed bloodstream infection; and a single retrospective study analyzed urinary tract infection. The production of evidence on risk factors Paediatric ICU has not kept up the same pace of that on adult - there are few studies with adequate design and statistical analysis. The methodological diversity of the studies did not allow for a summarized measurement of risk factors.


Toxocara in the mouse: a model for parasite-altered host behaviour?
The objective of this paper is to critically evaluate the significance of parasite-altered host behaviour in the Toxocara mouse model particularly in the light of the Manipulation Hypothesis. Murine behaviours were examined in both outbred and inbred strains of mice infected with different doses of Toxocara canis ova. Behaviours investigated included activity, exploration, response to novelty, anxiety, learning, memory and social behaviour. Subsequent modifications to the behaviour of infected mice were investigated with respect to dose administered and larval accumulation in the brain. There was substantial variation in the number of larvae recovered from brains of individual mice, which received similar doses of Toxocara ova. Furthermore, the numbers of larvae recovered at different doses differed significantly between an outbred and inbred strain of mouse. Alterations in infected host behaviour occurred and were related to the number of larvae recovered from the brain. For social behaviour in outbred mice, a high infection in the brain reduced levels of aggressive behaviour and increased levels of flight and defensive behaviours. In contrast, outbred mice with a low infection in the brain displayed a greater level of risk behaviour in respect of predator odour and the light/dark box compared to control or high infection mice. Post-infection, outbred mice were more immobile whereas inbred mice showed reduced immobility and increased digging and climbing. Impaired learning ability was observed in outbred mice with moderate and high levels of infection in the brain compared to control and low infection mice. Toxocara infection has an impact upon a diverse range of murine behaviours with little evidence for a specific and hence an adaptive alteration. Many of the effects on murine host behaviour by Toxocara are likely to be pathological side effects of infection rather than as a consequence of adaptive host-manipulation. Observed changes in murine behaviour may be relevant to human toxocariasis.


Growth promotion-related miRNAs in Oncidium orchid roots colonized by the endophytic fungus Piriformospora indica.
Piriformospora indica, an endophytic fungus of Sebacinales, colonizes the roots of a wide range of host plants and establishes various benefits for the plants. In this work, we describe miRNAs which are upregulated in Oncidium orchid roots after colonization by the fungus. Growth promotion and vigorous root development were observed in Oncidium hybrid orchid, while seedlings were colonized by P. indica. We performed a genome-wide expression profiling of small RNAs in Oncidium orchid roots either colonized or not-colonized by P. indica. After sequencing, 24,570,250 and 24744,141 clean reads were obtained from two libraries. 13,736 from 17,036,953 unique sequences showed homology to either 86 miRNA families described in 41 plant species, or to 46 potential novel miRNAs, or to 51 corresponding miRNA precursors. The predicted target genes of these miRNAs are mainly involved in auxin signal perception and transduction, transcription, development and plant defense. The expression analysis of miRNAs and target genes demonstrated the regulatory functions they may participate in. This study revealed that growth stimulation of the Oncidium orchid after colonization by P. indica includes an intricate network of miRNAs and their targets. The symbiotic function of P. indica on Oncidium orchid resembles previous findings on Chinese cabbage. This is the first study on growth regulation and development of Oncidium orchid by miRNAs induced by the symbiotic fungus P. indica.


Exposing the G-quadruplex to electric fields: the role played by telomeres in the propagation of DNA errors.
To protect their core machinery from the attack of exogenous agents, cells locate DNA in their nucleus. Nevertheless, some reactive chemical species and physical agents might reach DNA and alter its natural double helix structure. For instance, pulsed electric fields can be used to selectively rewrite the stored genetic information. However, for such modification to be effective, one needs, as a prerequisite, that the replication mechanism is not stopped by the field, so that the changes propagate over the following generations. Here, we use theoretical calculations to demonstrate that while such fields lead to permanent noncanonical Watson-Crick guanine-cytosine (GC) base pairs, the G-quadruplex motifs present in telomeres can more effectively preserve their native forms. Indeed, G-quadruplexes "resist" the perturbations induced by field strengths going up to 60 × 10-4 a.u., a figure constituting the upper limit before the complete destruction of the double helix architecture. Since the induced errors in the DNA base pairs are not transcribed into the telomeres, electric fields can indeed be used as a source of selective mutations in the genetic code.


Unique contributions of ISCOLE to the advancement of accelerometry in large studies.
Accelerometry has become a mainstay approach for objectively monitoring children's physical activity and sedentary time in epidemiological studies. The magnitude of effort underlying successful data collection, management and treatment is prodigious and its complexity has been associated with increasingly diverse methodological choices that, while defensible relative to specific research questions, conspire to undermine the ability to compare results between studies. Although respecting widespread calls for best practices, it is also important to openly share tools and resources supporting potential improvements to research practice and study design, thus allowing others to replicate, further improve, and/or otherwise build on this foundation. The International Study of Childhood Obesity, Lifestyle and the Environment (ISCOLE) is a large multinational study that included accelerometer-based measures of physical activity, sedentary time and sleep. This review summarizes the unique contributions of ISCOLE to the advancement of accelerometry in large studies of children's behavior, and in particular: (1) open-access publication of the ISCOLE accelerometry Manual of Operations; (2) 24-h waist-worn accelerometry protocol; (3) identification and extraction of nocturnal total sleep episode time (with open access to editable SAS syntax); (4) development of the first interpretive infrastructure for identifying and defining an evolved list of sleep-related variables from 24-h waist-worn accelerometry; (5) provision of a detailed model for reporting accelerometer paradata (administrative data related to accelerometry); and (6) cataloging the most detailed and defensible list of accelerometry-derived physical activity and sedentary time variables to date. The novel tools and resources associated with these innovations are shared openly in an effort to support methodological harmonization and overall advancement of accelerometry in large epidemiological studies.


Effect of biaxiality on chirality in chiral nematic liquid crystals.
Biaxiality and chirality are two of the most interesting topics in materials and biological science, particularly in liquid crystals. What is even more interesting is that these two properties are related. It was theoretically predicted that morphological chirality is impossible without morphological biaxiality in chiral nematic liquid crystals. We experimentally study the effect of biaxiality on chirality. We show that when achiral liquid crystal dimers with large molecular biaxiality are doped into chiral nematic liquid crystals, their helical pitch is significantly decreased. We have also observed an abnormal fingerprint texture of the chiral nematic liquid crystal doped dimers, which suggests morphological biaxiality. Our experimental results support the biaxial theory of chiral nematic liquid crystals.


A High Resolution Study of Dynamic Changes of Ce2O3 and CeO2 Nanoparticles in Complex Environmental Media.
Ceria nanoparticles (NPs) rapidly and easily cycle between Ce(III) and Ce(IV) oxidation states, making them prime candidates for commercial and other applications. Increased commercial use has resulted in increased discharge to the environment and increased associated risk. Once in complex media such as environmental waters or toxicology exposure media, the same redox transformations can occur, causing altered behavior and effects compared to the pristine NPs. This study used high resolution scanning transmission electron microscopy and electron energy loss spectroscopy to investigate changes in structure and oxidation state of small, polymer-coated ceria suspensions in complex media. NPs initially in either the III or IV oxidation states, but otherwise identical, were used. Ce(IV) NPs were changed to mixed (III, IV) NPs at high ionic strengths, while the presence of natural organic macromolecules (NOM) stabilized the oxidation state and increased crystallinity. The Ce(III) NPs remained as Ce(III) at high ionic strengths, but were modified by the presence of NOM, causing reduced crystallinity and degradation of the NPs. Subtle changes to NP properties upon addition to environmental or ecotoxicology media suggest that there may be small but important effects on fate and effects of NPs compared to their pristine form.


The value of wet leaves.
Contents Summary 1156 I. Introduction 1156 II. How often are leaves wet? 1157 III. The costs of leaf wetting 1157 IV. The real and potential benefits of leaf wetting 1161 V. Wet leaves: costs, benefits and tradeoffs in a changing world 1165 Acknowledgements 1166 References 1166 SUMMARY: An often-overlooked feature of all plants is that their leaf surfaces are wet for significant periods over their lifetimes. Leaf wetting has a number of direct and indirect effects on plant function from the scale of the leaf to that of the ecosystem. The costs of leaf wetting for plant function, such as the growth of pathogens and the leaching of nutrients, have long been recognized. However, an emerging body of research has also begun to demonstrate some very clear benefits. For instance, leaf wetting can improve plant-water relations and lead to increased photosynthesis. Leaf wetting may also lead to synergistic effects on plant function, such as when leaf water potential improvements lead to enhanced growth that does not occur when plant leaves are dry. We identify important reasons why leaf wetting can be critical for plant sciences to not only acknowledge, but also directly address, in future research. To do so, we provide a framework for the consideration of the relative balance of the various costs and benefits resulting from leaf wetting, as well as how this balance may be expected to change given projected scenarios of global climate change in the future.


Treatment-related gastrointestinal toxicities and advanced colorectal or pancreatic cancer: A critical update.
Gastrointestinal toxicities (GIT), including oral mucositis, nausea and vomiting, and diarrhea, are common side effects of chemotherapy and targeted agents in patients with advanced colorectal cancer and pancreatic cancer. Being often underreported, it is still difficult to precisely establish their burden in terms of both patient's quality of life and cancer care costs. Moreover, with the use of more intensive upfront combination regimens, the frequency of these toxicities is rapidly growing with a potential negative effect also on patient's outcome, as a result of dose reductions, delays or even discontinuation of active treatments. Thus, identifying patients at higher risk of developing GIT as well as an optimal management are paramount in order to improve patient's compliance and outcome. After the description of the main treatment-induced GIT, we discuss the current knowledge on the pathophysiology of these side effects and comment the scales commonly used to assess and grade them. We then provide a critical update on GIT incidence based on the results of key randomized trials conducted in patients with metastatic colorectal cancer and advanced pancreatic cancer.


Modulation depth threshold in the Compensation Comparison approach.
Recently, the "Compensation Comparison" method was introduced for measuring retinal straylight. In this article, basic aspects are described, in particular a generalization of the approach using the concept of "precompensation," and including flicker threshold as parameter in the psychophysical model. The model was experimentally verified in lab measurements with and without artificially increased straylight and was tested on the data from the multi-center GLARE study. The resulting flicker threshold estimates were analyzed to better understand their origin. An effect of flicker adaptation over distance was found. The new approach proved suitable to describe Compensation Comparison measurements including precompensation, and also for subjects with poor psychometric behavior.


Porous polymer films templated by marangoni flow-induced water droplet arrays.
In this article, we report the development of a novel, simple, and cost-effective method for fabricating porous polymer films with controllable interpore distances, pore sizes, and arrangements using water droplets induced by Marangoni flow as templates. First, a spread-thin ethanol film on a partially water-wettable substrate is exposed to a humid airflow, facilitating the evaporation and recession of the ethanol film. Meanwhile, water in the airflow condenses on the ethanol film and accumulates near the receding contact line, which induces the formation of water fingers at the receding contact line and, finally, ordered arrays of water droplets after detachment. The formation of the hexagonal and square arrays of water droplets is due to the pinning and sliding of the water fingers on the silicone oxide (SiOx) and silicon (Si) substrates, respectively. By varying the thickness of the ethanol film spread on the Si substrate, the sliding velocity of water fingers can be tuned, subsequently leading to the fabrication of other arrangements. The interdroplet distance and droplet size can be dependently controlled by tuning the humidity of the airflow. The ordered arrays of water droplets on the substrate are then utilized to fabricate porous polymer films by dip-coating the substrate with a polystyrene solution. Films with hexagonal and square (and other arrangements) arrays of pores are fabricated on the silicon oxide (SiOx) and silicon (Si) substrates, respectively. The pore size can also be independently tuned by further condensation or evaporation of formed water droplets, leading to porous polymer films with both close- and non-close-packed arrays of pores. The ordered porous polymer films can be further used as templates for fabricating metal post patterns.


Racial differences in discrimination experiences and responses among minority substance users.
Discrimination is associated with both mental and physical health, and may be a particularly important determinant of health among marginalized groups. This study assessed differences in discrimination experiences and responses to discrimination between Black and Latino active substance users in New York City. 500 Black and 419 Latino active substance users were recruited through outreach workers, service agencies, and word of mouth. We collected data about different types of discrimination experienced (eg, discrimination due to race, gender, substance use), the domains in which it occurred (eg, at work, with police), and participants' responses to unfair treatment. Discrimination due to drug use was the most commonly reported type of discrimination among both Blacks and Latinos. Black respondents were more likely than Latinos to report discrimination due to their drug use (79% to 70%), race (39% to 23%), poverty (38% to 26%), gender (18% to 9%), and sexual orientation (38% to 6%). However, among those reporting discrimination due to drug use, Latinos experienced more rejection from family (81% to 70%), friends (73% to 60%), police (86% to 79%), employers (72% to 56%), and medical care professionals (29% to 18%). Black respondents were more likely to respond actively to discrimination, whereas Latino respondents were more likely to internalize experiences. Substantial differences exist in discrimination experiences and responses to discrimination between Black and Latino substance users. These differences may help explain racial and ethnic differences in health among marginalized populations, and identify avenues for effective, targeted intervention.


Identifying the Hamiltonian structure in linear response theory.
We present a unifying framework for linear response eigenvalue equations that encompasses both variational Hartree-Fock and Kohn-Sham density functional theory as well as non-variational coupled-cluster theory. The joint description is rooted in the so-called Hamiltonian structure of the response kernel matrices, whose properties permit an immediate identification of the well-known paired eigenvalue spectrum describing a molecule in the isolated state. Recognizing the Hamiltonian structure underlying the equations further enables a generalization to the case of a polarizable-embedded molecule treated in variational and, in particular, in non-variational theories.


Polarization properties of degenerate four-wave mixing in flame OH.
The polarization properties of backward-box, degenerate four-wave mixing from OH molecules are measured in a flame and compared with theory. Ratios of signal intensities for different laser polarizations are shown to exceed perturbation-theory predictions for a closed two-level system when optical intensity gratings are formed in the interaction volume. These results are shown to be inconsistent with population-nonconserving effects and are attributed to scattering from quenching-induced thermal density gratings.


Key Role of ROS in the Process of 15-Lipoxygenase/15-Hydroxyeicosatetraenoiccid-Induced Pulmonary Vascular Remodeling in Hypoxia Pulmonary Hypertension.
We previously reported that 15-lipoxygenase (15-LO) and its metabolite 15-hydroxyeicosatetraenoic acid (15-HETE) were up-regulated in pulmonary arterial cells from both pulmonary artery hypertension patients and hypoxic rats and that these factors mediated the progression of pulmonary hypertension (PH) by affecting the proliferation and apoptosis of pulmonary arterial (PA) cells. However, the underlying mechanisms of the remodeling induced by 15-HETE have remained unclear. As reactive oxygen species (ROS) and 15-LO are both induced by hypoxia, it is possible that ROS are involved in the events of hypoxia-induced 15-LO expression that lead to PH. We employed immunohistochemistry, tube formation assays, bromodeoxyuridine (BrdU) incorporation assays, and cell cycle analyses to explore the role of ROS in the process of 15-HETE-mediated hypoxic pulmonary hypertension (HPH). We found that exogenous 15-HETE facilitated the generation of ROS and that this effect was mainly localized to mitochondria. In particular, the mitochondrial electron transport chain and nicotinamide-adenine dinucleotide phosphate oxidase 4 (Nox4) were responsible for the significant 15-HETE-stimulated increase in ROS production. Moreover, ROS induced by 15-HETE stimulated endothelial cell (EC) migration and promoted pulmonary artery smooth muscle cell (PASMC) proliferation under hypoxia via the p38 MAPK pathway. These results indicated that 15-HETE-regulated ROS mediated hypoxia-induced pulmonary vascular remodeling (PVR) via the p38 MAPK pathway.


A comprehensive review of partial anterior cruciate ligament tears.
A partial tear of the anterior cruciate ligament is characterized by an asymmetric Lachman-test result, a negative pivot-shift test, a low-grade KT-1000 arthrometer measurement (< or =3 mm), and arthroscopic evidence of anterior cruciate ligament injury. The pivot shift test is the most important test in determining anterior cruciate ligament insufficiency. A positive test, independent of the grade, is indicative of a functionally deficient anterior cruciate ligament. Nonoperative management results in an acceptable clinical outcome in the majority of cases. Progression to knee instability (anterior translation and rotation) depends on the extent of the anterior cruciate ligament injury and the activity level of the patient. Thermal treatment is not recommended for partial tears of the anterior cruciate ligament. Symptomatic instability is treated reliably with anterior cruciate ligament reconstruction.


DISC1 (disrupted-in-schizophrenia-1) regulates differentiation of oligodendrocytes.
Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a translocation, t(1;11) (q42.1;q14.3), that segregates with major psychiatric disorders, including schizophrenia, recurrent major depression and bipolar affective disorder, in a Scottish family. Here we report that mammalian DISC1 endogenously expressed in oligodendroglial lineage cells negatively regulates differentiation of oligodendrocyte precursor cells into oligodendrocytes. DISC1 expression was detected in oligodendrocytes of the mouse corpus callosum at P14 and P70. DISC1 mRNA was expressed in primary cultured rat cortical oligodendrocyte precursor cells and decreased when oligodendrocyte precursor cells were induced to differentiate by PDGF deprivation. Immunocytochemical analysis showed that overexpressed DISC1 was localized in the cell bodies and processes of oligodendrocyte precursor cells and oligodendrocytes. We show that expression of the myelin related markers, CNPase and MBP, as well as the number of cells with a matured oligodendrocyte morphology, were decreased following full length DISC1 overexpression. Conversely, both expression of CNPase and the number of oligodendrocytes with a mature morphology were increased following knockdown of endogenous DISC1 by RNA interference. Overexpression of a truncated form of DISC1 also resulted in an increase in expression of myelin related proteins and the number of mature oligodendrocytes, potentially acting via a dominant negative mechanism. We also identified involvement of Sox10 and Nkx2.2 in the DISC1 regulatory pathway of oligodendrocyte differentiation, both well-known transcription factors involved in the regulation of myelin genes.


Feedback of Individual Genetic Results to Research Participants: Is It Feasible in Europe?
There is growing consensus that individual genetic research results that are scientifically robust, analytically valid, and clinically actionable should be offered to research participants. However, the general practice in European research projects is that results are usually not provided to research participants for many reasons. This article reports on the views of European experts and scholars who are members of the European COST Action CHIP ME IS1303 (Citizen's Health through public-private Initiatives: Public health, Market and Ethical perspectives) regarding challenges to the feedback of individual genetic results to research participants in Europe and potential strategies to address these challenges. A consultation of the COST Action members was conducted through an email survey and a workshop. The results from the consultation were analyzed following a conventional content analysis approach. Legal frameworks, professional guidelines, and financial, organizational, and human resources to support the feedback of results are largely missing in Europe. Necessary steps to facilitate the feedback process include clarifying legal requirements to the feedback of results, developing harmonized European best practices, promoting interdisciplinary and cross-institutional collaboration, designing educational programs and cost-efficient IT-based platforms, involving research ethics committees, and documenting the health benefits and risks of the feedback process. Coordinated efforts at pan-European level are needed to enable equitable, scientifically sound, and socially robust feedback of results to research participants.


Several selective protein kinase C inhibitors including procyanidins promote hair growth.
We have previously reported that procyanidin oligomers selectively promote growth of murine hair epithelial cells in vitro and stimulate anagen induction in vivo. We report here the possible relationship between the protein kinase C-inhibiting activity of procyanidins and their hair-growing activity. Of the procyanidins, procyanidin B-2 and procyanidin C-1, which selectively inhibit protein kinase C, intensively promote hair epithelial cell proliferation in vitro and stimulate anagen induction in vivo. On the other hand, procyanidins, which inhibit both protein kinase C and A, showed relatively low activity in in vitro and in vivo evaluations. We also found that calphostin C, which is a selective inhibitor of protein kinase C, possesses hair epithelial cell growth-promoting activity in vitro and anagen phase-inducing hair-growing activity in vivo. Other selective protein kinase C inhibitors, such as hexadecylphosphocholine, palmitoyl-DL-carnitine chloride, and polymyxin B sulfate, also show marked anagen phase-inducing hair-growing activity in vivo. Nonselective protein kinase inhibitors, such as staurosporine and K252a, inhibit the growth of hair epithelial cells. 1,2-Dioctanoyl-sn-glycerol, a protein kinase C activator, dose-dependently decreases the growth of hair epithelial cells. Forskolin, an adenylate cyclase activator, promotes hair epithelial cell growth and boosts the growth-promoting effect of procyanidin B-2. It is speculated that the hair-growing activity of procyanidins is related to their protein kinase C-inhibiting activity.


First Report of Occurrence of Papaya ring spot virus Infecting Papaya in Bangladesh.
Papaya (Carica papaya L.) is an important fruit crop in Bangladesh. During surveys conducted in Dhaka and Mymensingh regions from April to June 2003, >50% of papaya plants were observed to have leaf mottling, mosaic and mild distortion, and water-soaked streaks on petioles and stem, which are typical symptoms of Papaya ring spot virus (PRSV) infection. Electron-microscopic examination of negatively stained leaf-dip preparations from 10 symptomatic samples revealed the association of flexuous virus particles that were decorated with polyclonal antibodies raised to an isolate from India (PRSV-D). The identity of PRSV associated with the papaya disease in Bangladesh was further confirmed by reverse transcription polymerase chain reaction and sequence analysis (2). By using PRSV specific primers (2), the 3'-terminal region comprising a part of the nuclear inclusion b gene, the coat protein (CP) gene, and the untranslated region were amplified and sequenced (GenBank Accession No. AY423557). The CP gene consisted of 286 amino acids and the conserved regions common to the genus Potyvirus, such as WCIEN and QMKAA, were present. Like all known PRSV sequences (1), a stretch of glutamic acid and lysine repeats (EK region) after the aphid transmission motif (DAG) also was present. Comparative CP amino acid sequence analyses revealed that the virus infecting papaya in Bangladesh, designated as PRSV-Bd, shared 89 to 92% identity with PRSV isolates from India and 88 to 93% identity with isolates from other parts of the world. To our knowledge, this is the first report of occurrence of PRSV infecting papaya in Bangladesh. References: (1) M. F. Bateson et al. J. Gen. Virol. 83:2575, 2002. (2) R. K. Jain et al. Ann Appl. Biol. 132:413, 1998.


Role of shear stress and endothelial prostaglandins in flow- and viscosity-induced dilation of arterioles in vitro.
We have studied the effect of changes in shear stress on diameter of isolated arterioles of rat cremaster muscle. The steady-state active diameter of arterioles at a constant perfusion pressure (60 mm Hg) was 80 +/- 1.2 microns. The vessels' passive diameter (Ca(2+)-free solution) was 156 +/- 1.8 microns. Changes in shear stress were induced either by an increase in flow (velocity) or by an increase in viscosity of the perfusion solution. At a constant perfusion pressure, the stepwise increase in perfusion flow (0-80 microliters/min in 10-microliters/min steps) elicited, with a delay of approximately 20 seconds, a gradual increase in diameter up to 46%. At a constant 20-microliters/min flow rate, increases in viscosity of the perfusate (2%, 4%, and 6% dextran [molecular weight, 77,800]) caused a gradual vasodilation up to 22%. Varying flow and viscosity of the perfusate simultaneously resulted in an upward shift of the flow-diameter curve. Both flow- and viscosity-induced dilations were eliminated by the removal of the endothelium of arterioles (by air) or were inhibited by indomethacin (10(-5) M). The efficacy and specificity of these inhibitory treatments were assessed with vasoactive agents whose action, with regard to endothelial mediation, has been determined previously. The arteriolar dilation maintained calculated wall shear stress close to control values during increases in flow and/or viscosity of the perfusate, but when the dilation was inhibited by removal of the endothelium or by indomethacin, wall shear stress increased significantly in a cumulative manner.(ABSTRACT TRUNCATED AT 250 WORDS)


Review of the use of physical restraints and lap belts with wheelchair users.
Wheelchair-related physical restraints, lap belts, and other alternatives are intended to provide safe and adequate seating and mobility for individuals using wheelchairs. Physical restraints and lap belts are also helpful for positioning people in their wheelchairs to reduce the risk of injury during wheelchair tips and falls. However, when used improperly or in ways other than intended, injury or even death can result. Although widely prescribed, little evidence is available to direct professionals on the appropriate use of these restraints and lap belts and for whom these restraints are indicated. The purpose of this study was to conduct a review of available literature from 1966-2006 to identify the risks and benefits associated with lap belts while seated in wheelchairs. Twenty-five studies that met the inclusion criteria were reviewed. Nine studies reported the frequency of asphyxial deaths caused by physical restraints, nine studies reported the long-term complication and indirect adverse effects of physical restraints and lap-belt use, and seven studies reported the benefits of physical restraints and lap belts with individuals using wheelchairs. Despite the weak evidence, the results suggest a considerable number of deaths from asphyxia caused by the use of physical restraints occurred each year in the U.S. The majority of the deaths occurred in nursing homes, followed by hospitals, and then the home of the person. Most deaths occurred while persons were restrained in wheelchairs or beds. Based on that, caution needs to be exercised when using restraints or positioning belts. In addition, other seating and environment alternatives should be explored prior to using restraints or positioning belts, such as power wheelchair seating options. Positioning belts may reduce risk of falls from wheelchairs and should be given careful consideration, but caution should be exercised if the individual cannot open the latch independently. Also, the duration of use of the physical restraint should be limited. Therefore, several factors should be considered when devising a better quality of physical-restraint services provided by health care professionals. These efforts can lead to improved safety and quality of life for individuals who use wheelchairs.


Non-Phosphorylated Tau in Cerebrospinal Fluid is a Marker of Alzheimer's Disease Continuum in Young Urbanites Exposed to Air Pollution.
Long-term exposure to fine particulate matter (PM2.5) and ozone (O3) above USEPA standards is associated with Alzheimer's disease (AD) risk. Metropolitan Mexico City (MMC) children exhibit subcortical pretangles in infancy and cortical tau pre-tangles, NFTs, and amyloid phases 1-2 by the 2nd decade. Given their AD continuum, we measured in 507 normal cerebrospinal fluid (CSF) samples (MMC 354, controls 153, 12.82±6.73 y), a high affinity monoclonal non-phosphorylated tau antibody (non-P-Tau), as a potential biomarker of AD and axonal damage. In 81 samples, we also measured total tau (T-Tau), tau phosphorylated at threonine 181 (P-Tau), amyloid-β1-42, BDNF, and vitamin D. We documented by electron microscopy myelinated axonal size and the pathology associated with combustion-derived nanoparticles (CDNPs) in anterior cingulate cortex white matter in 6 young residents (16.25±3.34 y). Non-P-Tau showed a strong increase with age significantly faster among MMC versus controls (p = 0.0055). Aβ1 - 42 and BDNF concentrations were lower in MMC children (p = 0.002 and 0.03, respectively). Anterior cingulate cortex showed a significant decrease (p = <0.0001) in the average axonal size and CDNPs were associated with organelle pathology. Significant age increases in non-P-Tau support tau changes early in a population with axonal pathology and evolving AD hallmarks in the first two decades of life. Non-P-Tau is an early biomarker of axonal damage and potentially valuable to monitor progressive longitudinal changes along with AD multianalyte classical CSF markers. Neuroprotection of young urbanites with PM2.5 and CDNPs exposures ought to be a public health priority to halt the development of AD in the first two decades of life.


Phonological aspects of word recognition as revealed by high-resolution spatio-temporal brain mapping.
We describe, for the first time, the use of high-resolution event-related brain potentials (hrERP) to identify the spatio-temporal characteristics of neural systems involved in phonological analysis. Subjects studied a visual word/non-word that was followed by the brief presentation of a prime letter (e.g. House, M) with the instruction to anticipate the word/non-word formed by replacing the word's first letter with the prime letter. After the prime letter, an auditory target word/non-word was presented that either matched/mismatched expectations (e.g., Mouse/Barn). ERPs were recorded to the onset of the auditory targets and scalp topographical maps were derived for the phonological mismatch negativity (PMN). The PMN reflected phonological analysis and examination of the peak topography revealed that the response was characterized by a prominent frontal, right-asymmetrical distribution. Spatial de-blurring (using current source density maps) indicated that the PMN scalp topography resulted primarily from an active left anterior source. The current results provide the initial evidence for the localization of the intra-cranial generator(s) involved in phonological analysis.


Distress Calls of a Fast-Flying Bat (Molossus molossus) Provoke Inspection Flights but Not Cooperative Mobbing.
Many birds and mammals produce distress calls when captured. Bats often approach speakers playing conspecific distress calls, which has led to the hypothesis that bat distress calls promote cooperative mobbing. An alternative explanation is that approaching bats are selfishly assessing predation risk. Previous playback studies on bat distress calls involved species with highly maneuverable flight, capable of making close passes and tight circles around speakers, which can look like mobbing. We broadcast distress calls recorded from the velvety free-tailed bat, Molossus molossus, a fast-flying aerial-hawker with relatively poor maneuverability. Based on their flight behavior, we predicted that, in response to distress call playbacks, M. molossus would make individual passing inspection flights but would not approach in groups or approach within a meter of the distress call source. By recording responses via ultrasonic recording and infrared video, we found that M. molossus, and to a lesser extent Saccopteryx bilineata, made more flight passes during distress call playbacks compared to noise. However, only the more maneuverable S. bilineata made close approaches to the speaker, and we found no evidence of mobbing in groups. Instead, our findings are consistent with the hypothesis that single bats approached distress calls simply to investigate the situation. These results suggest that approaches by bats to distress calls should not suffice as clear evidence for mobbing.


Electroencephalographic reactivity as predictor of neurological outcome in postanoxic coma: A multicenter prospective cohort study.
Outcome prediction in patients after cardiac arrest (CA) is challenging. Electroencephalographic reactivity (EEG-R) might be a reliable predictor. We aimed to determine the prognostic value of EEG-R using a standardized assessment. In a prospective cohort study, a strictly defined EEG-R assessment protocol was executed twice per day in adult patients after CA. EEG-R was classified as present or absent by 3 EEG readers, blinded to patient characteristics. Uncertain reactivity was classified as present. Primary outcome was best Cerebral Performance Category score (CPC) in 6 months after CA, dichotomized as good (CPC = 1-2) or poor (CPC = 3-5). EEG-R was considered reliable for predicting poor outcome if specificity was ≥95%. For good outcome prediction, a specificity of ≥80% was used. Added value of EEG-R was the increase in specificity when combined with EEG background, neurological examination, and somatosensory evoked potentials (SSEPs). Of 160 patients enrolled, 149 were available for analyses. Absence of EEG-R for poor outcome prediction had a specificity of 82% and a sensitivity of 73%. For good outcome prediction, specificity was 73% and sensitivity 82%. Specificity for poor outcome prediction increased from 98% to 99% when EEG-R was added to a multimodal model. For good outcome prediction, specificity increased from 70% to 89%. EEG-R testing in itself is not sufficiently reliable for outcome prediction in patients after CA. For poor outcome prediction, it has no substantial added value to EEG background, neurological examination, and SSEPs. For prediction of good outcome, EEG-R seems to have added value. ANN NEUROL 2019.


Genetic diversity of Chinese common bean (Phaseolus vulgaris L.) landraces assessed with simple sequence repeat markers.
Common beans were introduced from the Americas to China over 400 years ago and presently constitute an important export crop in many areas of the country. Evaluation of the genetic diversity present in Chinese accessions of common beans is essential for conservation, management and utilization of these genetic resources. The objective of this research was to evaluate a collection of 229 Chinese landraces with 30 microsatellite markers to evaluate the genetic variability, genepool identity and relationships within and between the groups identified among the genotypes. A total of 166 alleles were detected with an average of 5.5 alleles per locus for all microsatellites. The landraces were clustered into two genepools with two subgroups each. The level of diversity for Chinese landraces of Andean origin was higher than for the Chinese landraces of Mesoamerican origin due to the presence of more infrequent alleles in this first group. The range of marker prevalence indices was from 0.288 to 0.676 within the Andean group and from 0.426 to 0.754 within the Mesoamerican group. Two subgroups were identified in each genepool group with one of the Mesoamerican subgroups arising from introgression. Gene flow (Nm) was 0.86 or below between subgroups from different gene pools and 2.6 or above between subgroups within the genepools. We discuss the existence of a secondary center of diversity for common beans in China and the importance of inter genepool introgression.


End-of-life care for people dying with dementia in general practice in Belgium, Italy and Spain: A cross-sectional, retrospective study.
To describe and compare end-of-life care for people with mild or severe dementia in general practice in Belgium, Italy and Spain, in terms of place of care, place of death, treatment aims, use of specialized palliative care and communication with general practitioners (GPs). Cross-sectional retrospective survey was carried out of nationwide networks of GPs in Belgium, Italy and Spain, including patients who died aged 65 years or older in 2009-2011 and were judged by the GP to have had dementia (n = 1623). GPs reported a higher proportion of older people with severe dementia in Belgium (55%) than in Spain (46 %) and Italy (45 %), and a higher proportion of patients living in care homes (57% vs 18% and 13%, respectively). A palliative treatment aim was common in the last 3 months of life in all three countries. Specialized palliative care services were provided in 14% (Italy, severe dementia) to 38% (Belgium, severe dementia) of cases. Communication between GP and patient about illness-related topics occurred in between 50% (Italy) and 72% (Belgium) of cases of mild dementia, and 10% (Italy) to 32% (Belgium) of cases of severe dementia. Patient preferences for end-of-life care were known in a minority of cases. Few people (13-15 %) were transferred between care settings in the last week of life. Although overall treatment aims at the end of life are often aligned with a palliative care approach and transfer rates are low, there is room for improvement in end-of-life care for people with dementia in all countries studied, especially regarding early patient-GP communication. Geriatr Gerontol Int 2017; 17: 1667-1676.


Differential basolateral-apical distribution of scavenger receptor, class B, type I in cultured cells and the liver.
The high-density lipoprotein (HDL) receptor, scavenger receptor class B, type I (SR-BI), mediates selective cholesteryl ester uptake into the liver, which finally results in cholesterol secretion into the bile. Despite several reports, the distribution of hepatic SR-BI between the sinusoidal and canalicular membranes is still under debate. We present immunohistological data using specific markers showing that the bulk of SR-BI is present in sinusoidal membranes and, to a lesser extent, in canalicular membranes in murine and human liver sections. In addition, SR-BI was detected in preparations of rat liver canalicular membranes. We also compared the in vivo findings to HepG2 cells, a widely used in vitro hepatocyte model. Interestingly, SR-BI was enriched in bile canalicular-like (BC-like) structures in polarized HepG2 cells, which were cultivated either conventionally to form a monolayer or in Matrigel to form three-dimensional structures. Fluorescently labeled HDL was transported into close proximity of BC-like structures, whereas HDL labeled with the fluorescent cholesterol analog BODIPY-cholesterol was clearly detected within these structures. Importantly, similarly to human and mouse liver, SR-BI was localized in basolateral membranes in three-dimensional liver microtissues from primary human liver cells. Our results demonstrate that SR-BI is highly enriched in sinusoidal membranes and is also found in canalicular membranes. There was no significant basolateral-apical redistribution of hepatic SR-BI in fasting and refeeding experiments in mice. Furthermore, in vitro studies in polarized HepG2 cells showed explicit differences as SR-BI was highly enriched in BC-like structures. These structures are, however, functional and accumulated HDL-derived cholesterol. Thus, biological relevant model systems should be employed when investigating SR-BI distribution in vitro.


Identification of minimal predictors of avian pathogenic Escherichia coli virulence for use as a rapid diagnostic tool.
To identify traits that predict avian pathogenic Escherichia coli (APEC) virulence, 124 avian E. coli isolates of known pathogenicity and serogroup were subjected to virulence genotyping and phylogenetic typing. The results were analyzed by multiple-correspondence analysis. From this analysis, five genes carried by plasmids were identified as being the most significantly associated with highly pathogenic APEC strains: iutA, hlyF, iss, iroN, and ompT. A multiplex PCR panel targeting these five genes was used to screen a collection of 994 avian E. coli isolates. APEC isolates were clearly distinguished from the avian fecal E. coli isolates by their possession of these genes, suggesting that this pentaplex panel has diagnostic applications and underscoring the close association between avian E. coli virulence and the possession of ColV plasmids. Also, the sharp demarcation between APEC isolates and avian fecal E. coli isolates in their plasmid-associated virulence gene content suggests that APEC isolates are well equipped for a pathogenic lifestyle, which is contrary to the widely held belief that most APEC isolates are opportunistic pathogens. Regardless, APEC isolates remain an important problem for poultry producers and a potential concern for public health professionals, as growing evidence suggests a possible role for APEC in human disease. Thus, the pentaplex panel described here may be useful in detecting APEC-like strains occurring in poultry production, along the food chain, and in human disease. This panel may be helpful toward clarifying potential roles of APEC in human disease, ascertaining the source of APEC in animal outbreaks, and identifying effective targets of avian colibacillosis control.


Deficient EBV-specific B- and T-cell response in patients with chronic fatigue syndrome.
Epstein-Barr virus (EBV) has long been discussed as a possible cause or trigger of Chronic Fatigue Syndrome (CFS). In a subset of patients the disease starts with infectious mononucleosis and both enhanced and diminished EBV-specific antibody titers have been reported. In this study, we comprehensively analyzed the EBV-specific memory B- and T-cell response in patients with CFS. While we observed no difference in viral capsid antigen (VCA)-IgG antibodies, EBV nuclear antigen (EBNA)-IgG titers were low or absent in 10% of CFS patients. Remarkably, when analyzing the EBV-specific memory B-cell reservoir in vitro a diminished or absent number of EBNA-1- and VCA-antibody secreting cells was found in up to 76% of patients. Moreover, the ex vivo EBV-induced secretion of TNF-α and IFN-γ was significantly lower in patients. Multicolor flow cytometry revealed that the frequencies of EBNA-1-specific triple TNF-α/IFN-γ/IL-2 producing CD4(+) and CD8(+) T-cell subsets were significantly diminished whereas no difference could be detected for HCMV-specific T-cell responses. When comparing EBV load in blood immune cells, we found more frequently EBER-DNA but not BZLF-1 RNA in CFS patients compared to healthy controls suggesting more frequent latent replication. Taken together, our findings give evidence for a deficient EBV-specific B- and T-cell memory response in CFS patients and suggest an impaired ability to control early steps of EBV reactivation. In addition the diminished EBV response might be suitable to develop diagnostic marker in CFS.