The Nogo-B-PirB axis controls macrophage-mediated vascular remodeling.
Nogo-B mediates vascular protection and facilitates monocyte- and macrophage-dependent vascular remodeling. PirB is an alternate receptor for Nogo-B, but a role for the Nogo-PirB axis within the vascular system has not been previously reported. We examined whether Nogo-B or PirB play a role in regulating macrophage-mediated vascular remodeling and hypothesized that endothelial Nogo-B regulates vein graft macrophage infiltration via its alternate receptor PirB. Vein grafts were performed using Nogo and PirB wild type and knockout mice. Human vein grafts were similarly analyzed. The hindlimb ischemia model was performed in PirB wild type and knockout mice. Accompanying in vitro work included isolation of macrophages from PirB wild type and knockout mice. Increased Nogo-B and PirB mRNA transcripts and protein expression were observed within mouse and human vein grafts. Both Nogo knockout and PirB knockout vein grafts showed increased wall thickness and increased numbers of F4/80-positive macrophages. Macrophages derived from PirB knockout mice had increased adhesion to fibronectin, increased EC-specific binding, and increased numbers of mRNA transcripts of M2 markers as well as MMP3 and MMP9. PirB knockout vein grafts had increased active MMP9 compared to wild type vein grafts. PirB knockout mice had increased recovery from hindlimb ischemia and increased macrophage infiltration compared to wild type mice. Vein graft adaptation shows increased expression of both Nogo-B and PirB. Loss of PirB, or its endothelial ligand Nogo-B, results in increased inflammatory cell infiltration and vein graft wall thickening. These findings suggest that PirB regulates macrophage activity in vein grafts and that Nogo-B in the vein graft limits macrophage infiltration and vein graft thickening. PirB may play a more general role in regulating macrophage responses to vascular injury. Macrophage inhibition via Nogo-PirB interactions may be an important mechanism regulating vein graft adaptation to the arterial circulation.


Neonatology and the Environment: Impact of Early Exposure to Airborne Environmental Toxicants on Infant and Child Neurodevelopment.
Environmental contaminants pose a threat to infant neurodevelopment. In this current paper, we discuss evidence for the potentially harmful impact of fetal and early childhood exposure to polycyclic aromatic hydrocarbons (PAHs), environmental tobacco smoke (ETS), and organophosphorus (OP) insecticides. We focus on effects resulting from chronic and low-level exposure during the prenatal period and early childhood, when the brain is still undergoing rapid developmental changes.


Remote Supervision in Short-Term Global Health Experiences.
The global health development community is increasingly examining the phenomenon of short-term experiences in global health (STEGH), with an aim to mitigate the negative impacts of such activities on host communities. Appropriate supervision is one strategy, but various barriers (e.g., institutional requirements) limit the availability of qualified supervisors. Remote supervision represents one potential model to provide supervision that may mitigate the negative impacts of STEGH. This paper reports observed outcomes from a description of a pilot remote supervision program employed in a global health program for Canadian undergraduate students. Benefits for learners included greater confidence and independence, greater perceived effectiveness in conducting their project abroad, and reassurance of remote support from their supervisor, supplemented with day-to-day guidance from the local partner. Host communities reported greater trust in the bidirectional nature of partnership with the visiting institution, empowerment through directing students' work, and improved alignment of projects with community needs. Finally, faculty noted that remote supervision provided greater flexibility and freedom when compared to traditional in-person supervision, allowing them to maintain professional duties at home. Collectively, this pilot suggests that remote supervision demonstrates a potential solution to mitigating the harms of STEGHs undertaken by learners by providing adequate and appropriate remote supervision.


Selective IgA deficiency in autoimmune diseases.
Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Caucasians. It has previously been suggested to be associated with a variety of concomitant autoimmune diseases. In this review, we present data on the prevalence of IgAD in patients with Graves disease (GD), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), celiac disease (CD), myasthenia gravis (MG) and rheumatoid arthritis (RA) on the basis of both our own recent large-scale screening results and literature data. Genetic factors are important for the development of both IgAD and various autoimmune disorders, including GD, SLE, T1D, CD, MG and RA, and a strong association with the major histocompatibility complex (MHC) region has been reported. In addition, non-MHC genes, such as interferon-induced helicase 1 (IFIH1) and c-type lectin domain family 16, member A (CLEC16A), are also associated with the development of IgAD and some of the above diseases. This indicates a possible common genetic background. In this review, we present suggestive evidence for a shared genetic predisposition between these disorders.


Cryptosporidium Infection: Epidemiology, Pathogenesis, and Differential Diagnosis.
Cryptosporidium is a protozoan that infects a wide variety of vertebrates, including humans, causing acute gastroenteritis. The disease manifests with abdominal pain and diarrhea similar to that of choleric infection. In the immunocompromised hosts, the parasite causes prolonged infections that can also be fatal. For this reason, cryptosporidiosis is considered one of riskiest opportunistic infections for patients with acquired immunodeficiency syndrome. The best way to control the infection in these patients is setting up sensitive and specific diagnostic tests for epidemiological surveillance and morbidity reduction. Here, we summarized the general aspects of Cryptosporidium infection focusing on available diagnostic tools used for the diagnosis of cryptosporidiosis. Molecular methods currently available for its detection and progress in the development of new diagnostics for cryptosporidiosis are also discussed.


Fastball velocity trends in short-season minor league baseball.
Diminishing baseball velocities are objective measures to delineate pitching fatigue. Yet, velocity changes over the course of a competitive season vs. a single game remain unknown. This study examined fastball velocity (FBV) trends of minor league pitchers over an 8-game span. We assumed that accumulation of pitches would cause similar velocity decreases within games to produce velocity decreases between games pitched. Retrospective analysis of major league-affiliated pitching charts indicated mean FBVs, game pitches thrown, game innings pitched, rest days, and pitching work to rest ratios (PWRRs) for 12 pitchers over 8 games. Regression analyses (p < 0.05) were performed using the ordinary least squares method. The FBV was the dependent variable, where the explanatory variable was the game number (representing cumulative workload). Further analyses were performed on ball velocity differences predicted by days rest and PWRRs. The FBV increased linearly for the first 8 games of the season (R = 0.91, F(1,7) = 64.67, p < 0.001). Over the 8 - game period, mean FBVs increased 0.25 m/s (0.56 mph) with the greatest velocity increase occurring between the first and eighth game at 1.97 m/s (4.4 mph). Days rest and PWRRs did not impact FBV differences. When compared with previous research, minor league pitchers at the Class A Short Season level did not show similar exertion responses to cumulative workloads (pitches and innings pitched). Recovery factors (rest days, PWRRs, and training) also did not impact FBVs. Velocity increases may be attributable to biomechanical compensations, skill development, strength and conditioning regimens, multistarter rotations, and other performance-related factors. Strength and conditioning professionals should be aware of ball velocity trends, as apparent changes may infer neuromuscular fatigue and increased injury susceptibility, which require in-season training modifications.


Helicity locking of chiral light emitted from a plasmonic nanotaper.
Surface plasmon waves carry an intrinsic transverse spin, which is locked to its propagation direction. Apparently, when a singular plasmonic mode is guided on a conic surface this spin-locking may lead to a strong circular polarization of the far-field emission. Specifically, a plasmonic vortex excited on a flat metal surface propagates on an adiabatically tapered gold nanocone where the mode accelerates and finally beams out from the tip apex. The helicity of this beam is shown to be single-handed and stems solely from the transverse spin-locking of the helical plasmonic wave-front. We present a simple geometric model that fully predicts the emerging light spin in our system. Finally, we experimentally demonstrate the helicity-locking phenomenon by using accurately fabricated nanostructures and confirm the results with the model and numerical data.


Aromatic amides and ureas as novel molecular probes for diagnosing disease.
It is firmly established that control over the three-dimensional shape (i.e., the conformation) of aromatic amides and ureas can be achieved using a variety of methods, all of which rely on the addition of a substituent to a central nitrogen atom; exactly which conformation is adopted in solution can be determined using a variety of analytical techniques, such as: fluorescence, NMR and HPLC. We hypothesise that if the central nitrogen atoms were suitably functionalised with enzyme-cleavable groups, then the associated change in shape could be exploited upon the removal of a group, and these compounds could thus be exploited as diagnostic probes for the detection of analytes (i.e., enzymes) in solution or biological samples. The exquisite selectivity of naturally-occurring enzymes therefore makes it possible that the enzyme-cleavable group could be rationally designed and tailored for each enzyme of interest, thus making an analytical toolkit of diagnostic probes for detecting enzymes which are over-expressed in disease. If the sensitivity of such probes was sufficiently low enough, then they could potentially be used to detect the on-set of disease in a non-invasive manner from bodily fluids.


Cartilaginous epiphyses in extant archosaurs and their implications for reconstructing limb function in dinosaurs.
Extinct archosaurs, including many non-avian dinosaurs, exhibit relatively simply shaped condylar regions in their appendicular bones, suggesting potentially large amounts of unpreserved epiphyseal (articular) cartilage. This "lost anatomy" is often underappreciated such that the ends of bones are typically considered to be the joint surfaces, potentially having a major impact on functional interpretation. Extant alligators and birds were used to establish an objective basis for inferences about cartilaginous articular structures in such extinct archosaur clades as non-avian dinosaurs. Limb elements of alligators, ostriches, and other birds were dissected, disarticulated, and defleshed. Lengths and condylar shapes of elements with intact epiphyses were measured. Limbs were subsequently completely skeletonized and the measurements repeated. Removal of cartilaginous condylar regions resulted in statistically significant changes in element length and condylar breadth. Moreover, there was marked loss of those cartilaginous structures responsible for joint architecture and congruence. Compared to alligators, birds showed less dramatic, but still significant changes. Condylar morphologies of dinosaur limb bones suggest that most non-coelurosaurian clades possessed large cartilaginous epiphyses that relied on the maintenance of vascular channels that are otherwise eliminated early in ontogeny in smaller-bodied tetrapods. A sensitivity analysis using cartilage correction factors (CCFs) obtained from extant taxa indicates that whereas the presence of cartilaginous epiphyses only moderately increases estimates of dinosaur height and speed, it has important implications for our ability to infer joint morphology, posture, and the complicated functional movements in the limbs of many extinct archosaurs. Evidence suggests that the sizes of sauropod epiphyseal cartilages surpassed those of alligators, which account for at least 10% of hindlimb length. These data suggest that large cartilaginous epiphyses were widely distributed among non-avian archosaurs and must be considered when making inferences about locomotor functional morphology in fossil taxa.


Indoor residual spraying with micro-encapsulated pirimiphos-methyl (Actellic® 300CS) against malaria vectors in the Lake Victoria basin, Tanzania.
The indoor residual spraying programme for malaria vectors control was implemented in four districts of the Lake Victoria basin of Tanzania namely Ukerewe, Sengerema, Rorya andSerengeti. Entomological monitoring activities were implemented in one sentinel village in each district to evaluate the efficacy of pirimiphos-methyl 300 CS sprayed on different wall surfaces and its impact against malaria vectors post-IRS intervention. The residual decay rate of p-methyl 300 CS applied at a target dosage of 1g a.i./m2 on thesprayed wall surfaces was monitored for a period of 43 weeks post-IRSusing the WHO cone wall bioassay method. The bioassays were performed by exposing 2-5 days old unfed susceptible female Anopheles gambiae s.s. (Kisumu strain) to sprayed wall surfaces for a period of 30 minutes. In each sentinel village, mosquito collection was carried out by trained community mosquito collectors. Monthly mosquito collections were carried out from 6.00pm to 6.00am using CDC light traps and clay pot methods for indoors host seekingand outdoors resting mosquitoes respectively. Six traps (2 CDC light traps and 4 clay pots) were set per sentinel village per night for28 consecutive days in a moon. PCR and ELISA were used for mosquito species identification and sporozoite detection, respectively. Based on the WHOPES recommendation, insecticides should have a minimum efficacy of ≥ 80% mosquito mortality at 24 hours post exposure on the sprayed wall surfaces to be considered effective. In this study, p-methyl 300 CS was demonstrated to have a long residual efficacy of 21-43 weeks post-IRS on mud, cement, painted and wood wall surfaces. Numberof anopheline mosquitoes decreased post-IRS interventions in all sentinel villages. The highest numbers ofanopheline mosquitoes were collected in November-December, 38-43 weeks post-IRS. A total of 270 female anopheline mosquitoes were analyzed by PCR; out of which 236 (87.4%) were An. gambiae s.l. and 34 (12.6%) were An. funestus group. Of the 236 An. gambiae s.l.identified 12.6% (n = 34) were An. gambiae s.s. and 68.6% (n = 162) were An. arabiensis. Ofthe 34 An. funestus group indentified 91.2% (n = 31) were An. parensis and 8.8% (n = 3) were An. rivulorum. The overall Plasmodium falciparum sporozoite rate was 0.7% (n = 2,098). Pirimiphos-methyl 300 CS was found to be effective for IRS in the Lake Victoria basin,Tanzania. P-methyl 300 CShas a long residual efficacy on sprayed wall surfaces and therefore it is effective in controlling principal malaria vectors of An. gambiae s.l and An. funestus which rest on wall surfaces after and before feeding.


Prostaglandin E 2 Does Not Modulate CCR7 Expression and Functionality after Differentiation of Blood Monocytes into Macrophages.
Previously, we demonstrated that prostaglandin E2 (PGE2) induces C-C chemokine receptor type 7 (CCR7) expression on human monocytes, which stimulates their subsequent migration in response to the CCR7 natural ligands CCL19 and CCL21. In this study, we determined whether PGE2 affects CCR7 expression on macrophages. Flow cytometric analysis and chemotaxis assays were performed on Mono Mac-1-derived macrophage (MDMM-1) as well as unpolarized monocyte-derived macrophages (MDMs) to determine the CCR7 expression and functionality in the presence of PGE2. Data revealed that a MDMM-1 exhibited markedly downregulated CCR7 expression and functionality that were partially restored by treatment with PGE2. In MDMs, we observed a drastic downregulation of CCR7 expression and functionality that were unaffected following PGE2 treatment. Our data indicate that monocyte differentiation induces the loss of CCR7 expression and that PGE2 is unable to modulate CCR7 expression and functionality as shown previously in monocytes.


Ability of verbal autopsy data to detect deaths due to uncontrolled hyperglycaemia: testing existing methods and development and validation of a novel weighted score.
Verbal autopsy (VA) is a useful tool to ascertain cause of death where no other mechanisms exist. We aimed to assess the utility of VA data to ascertain deaths due to uncontrolled hyperglycaemia and to develop a weighted score (WS) to specifically identify cases. Cases were identified by a study or site physician with training in diabetes. These diagnoses were also compared with diagnoses produced by a standard computer algorithm (InterVA-4). This study was done using VA data from the Health and Demographic Survey sites in Agincourt in rural South Africa. Validation of the WS was done using VA data from Karonga in Malawi. All deaths from ages 1 to 49 years between 1992 and 2015 and between 2002 and 2016 from Agincourt and Karonga, respectively. There were 8699 relevant deaths in Agincourt and 1663 in Karonga. Of the Agincourt deaths, there were 77 study physician classified cases and 58 computer algorithm classified cases. Agreement between study physician classified cases and computer algorithm classified cases was poor (Cohen's kappa 0.14). Our WS produced a receiver operator curve with area under the curve of 0.952 (95% CI 0.920 to 0.985). However, positive predictive value (PPV) was below 50% when the WS was applied to the development set and the score was dominated by the necessity for a premortem diagnosis of diabetes. Independent validation showed the WS performed reasonably against site physician classified cases with sensitivity of 86%, specificity of 99%, PPV of 60% and negative predictive value of 99%. Our results suggest that widely used VA methodologies may be missing deaths due to uncontrolled hyperglycaemia. Our WS may offer improved ability to detect deaths due to uncontrolled hyperglycaemia in large populations studies where no other means exist.


The role of surface charge in the interaction of nanoparticles with model pulmonary surfactants.
Inhaled nanoparticles traveling through the airways are able to reach the respiratory zone of the lungs. In such an event, the incoming particles first come into contact with the liquid lining the alveolar epithelium, the pulmonary surfactant. The pulmonary surfactant is composed of lipids and proteins that are assembled into large vesicular structures. The question of the nature of the biophysicochemical interaction with the pulmonary surfactant is central to understand how the nanoparticles can cross the air-blood barrier. Here we explore the phase behavior of sub-100 nm particles and surfactant substitutes under controlled conditions. Three types of surfactant mimetics, including the exogenous substitute Curosurf®, a drug administered to infants with respiratory distress syndrome, are tested together with aluminum oxide (Al2O3), silicon dioxide (SiO2) and polymer (latex) nanoparticles. The main result here is the observation of spontaneous nanoparticle-vesicle aggregation induced by coulombic attraction. The role of the surface charges is clearly established. We also evaluate the supported lipid bilayer formation recently predicted and find that in the cases studied these structures do not occur. Pertaining to the aggregate internal structure, fluorescence microscopy shows that the vesicles and particles are intermixed at the nano- to microscale. With particles acting as stickers between vesicles, it is anticipated that the presence of inhaled nanomaterials in the alveolar spaces could significantly modify the interfacial and bulk properties of the pulmonary surfactant and interfere with lung physiology.


The influence of nearest-neighbour interactions and assembly dynamics on the transport properties of porphyrin supramolecular assemblies on Au(111).
Here we report on the effect of local molecular organization or "tertiary structure" on the charge transport properties of thiol-tethered tetraphenylporphyrin (ZnTPPF4-SC5SH) nanoscale clusters of ca. 5 nm in lateral dimension embedded within a dodecanethiol (C12) monolayer on Au(111). The structure of the clusters in the mixed monolayers and their resulting transport properties were monitored by Atomic Force Microscopy (AFM), Scanning Tunneling Microscopy (STM) and Spectroscopy (STS). The mixed films were deposited on Au(111) for a period of one to five days, during which the lateral dimensions of the ZnTPPF4-SC5SH islands that were formed after one day reduced by nearly 35% on average by five days, accompanied by a noticeable depletion of the surrounding C12 monolayer. These subtle changes in mixed monolayer morphology were accompanied by drastic differences in conductance. The ZnTPPF4-SC5SH clusters assembled for one day exhibited highly reproducible I-V spectra with simple tunneling behavior. By three days, this evolved into bias-induced switching of conductance, with a ∼100-1000 fold increase. Furthermore, current fluctuations started to become significant, and then dominated transport across the ZnTPPF4-SC5SH clusters assembled over five days. Our data suggests that this evolution can be understood by slow surface diffusion, enabling the ZnTPPF4-SC5SH molecules to overcome initial steric hindrance in the early stages of island formation in the C12 monolayer (at day one), to reach a more energetically-favored, close-packed organization, as noted by the decrease in island size (by day three). However, when desorption of the supporting matrix of C12 became pronounced (by day five), the ZnTPPF4-SC5SH clusters began to lose stabilization, and stochastic switching was then observed to dominate transport in the clusters, illustrating the critical nature of the local organization on these transport properties.


Mo/Si and Mo/Be multilayer thin films on Zerodur substrates for extreme-ultraviolet lithography.
Multilayer-coated Zerodur optics are expected to play a pivotal role in an extreme-ultraviolet (EUV) lithography tool. Zerodur is a multiphase, multicomponent material that is a much more complicated substrate than commonly used single-crystal Si or fused-silica substrates. We investigate the effect of Zerodur substrates on the performance of high-EUV reflectance Mo/Si and Mo/Be multilayer thin films. For Mo/Si the EUV reflectance had a nearly linear dependence on substrate roughness for roughness values of 0.06-0.36 nm rms, and the FWHM of the reflectance curves (spectral bandwidth) was essentially constant over this range. For Mo/Be the EUV reflectance was observed to decrease more steeply than Mo/Si for roughness values greater than approximately 0.2-0.3 nm. Little difference was observed in the EUV reflectivity of multilayer thin films deposited on different substrates as long as the substrate roughness values were similar.


Preventive and therapeutic effects of large-dose nicotinamide injections on diabetes associated with insulitis. An observation in nonobese diabetic (NOD) mice.
This experiment was undertaken to explore a novel method of therapy for insulin-dependent diabetes mellitus (IDDM), using nonobese diabetic (NOD) mice that had symptoms and histologic changes similar to those of human IDDM patients. We examined preventive and therapeutic effects of large-dose nicotinamide administration on diabetes in NOD mice. Eighteen young female NOD mice without glycosuria were randomly divided into two groups; nine received subcutaneous nicotinamide (0.5 mg/g body wt) injections every day and the other nine were maintained as a control group and not injected. After 40 days, all of the mice given nicotinamide showed almost normal glucose tolerance and only mild insulitis on histologic study. On the other hand, marked glycosuria and severe insulitis were observed in six of the nine mice not injected. Four of six NOD mice given nicotinamide from the day of the first occurrence of marked glycosuria displayed a disappearance of glycosuria and an improvement in glucose tolerance during the therapy; however, urine sugar became negative in only one of six mice that received nicotinamide from 1 to 2 wk after the onset of marked glycosuria. These results indicate that nicotinamide has preventive and therapeutic effects on diabetes in NOD mice, and suggest the reversibility of B-cell damage, at least at a very early stage of IDDM.


Dual affinity labeling of the active site of human lysozyme with an N-acetyllactosamine derivative: first ligand assisted recognition of the second ligand.
Among the three kinds of the 2',3'-epoxypropyl beta-glycoside of disaccharides (GlcNAc-beta1,4-GlcNAc, Gal-beta1,4-GlcNAc, and Man-beta1,4-GlcNAc), the derivative of N-acetyllactosamine (Gal-beta1,4-GlcNAc-Epo) caused the dual labeling of human lysozyme (HL) most efficiently. The labeled HL was crystallized and analyzed by X-ray diffraction methodology. The X-ray analysis located the two Gal-beta1,4-GlcNAc-Epo moieties inside the catalytic cleft of HL. The attachment sites were the side-chain carboxylate groups of the catalytic residues Glu35 and Asp53 in HL. The first Gal-beta1, 4-GlcNAc-Epo moiety occupied virtually the same position as observed in the HL labeled with single Gal-beta1,4-GlcNAc-Epo molecule. The second Gal-beta1,4-GlcNAc-Epo moiety was recognized via the carbohydrate-carbohydrate interaction with the first Gal-beta1, 4-GlcNAc-Epo moiety in addition to the protein-carbohydrate interaction with the "right-side" catalytic cleft of HL through a number of hydrogen bonds including water-mediated ones as well as many van der Waals contacts. The two N-acetylglucosamine residues stacked with each other, while the two rings of galactose residues approximately shared the same plane. The dual labeling with two Gal-beta1,4-GlcNAc-Epo molecules was supposed to have occurred sequentially, which was accompanied with the alteration to the pKa of Glu35 derived from the esterification of Asp53 in the first labeling. Both asymmetric carbons in the connection parts between HL and N-acetyllactosamine moieties showed the same stereoconfiguration derived from the reaction with (2'R) stereoisomer concerning the epoxide group in the labeling reagent. The results demonstrated that the HL labeled with single Gal-beta1,4-GlcNAc-Epo was functional as a novel N-acetyllactosamine-binding protein, and the second labeling was performed by way of the first-ligand assisted recognition of the second ligand.


Short-Term Effect of Autogenic Drainage on Ventilation Inhomogeneity in Adult Subjects With Stable Non-Cystic Fibrosis Bronchiectasis.
Lung clearance index (LCI), a measure of ventilation inhomogeneity derived from a multiple-breath washout test, is a promising tool for assessing airway function in patients with non-cystic fibrosis bronchiectasis. However, it is unknown whether ventilation inhomogeneity could improve after successful elimination of excessive secretions within bronchiectasis. The objective of this work was to assess the short-term effects of lung secretion clearance using the autogenic drainage technique on standard lung function tests and LCI in subjects with non-cystic fibrosis bronchiectasis. Nitrogen-based multiple-breath washout, spirometry, and body plethysmography tests were performed 30 min before autogenic drainage in adults with stable non-cystic fibrosis bronchiectasis. The autogenic drainage session was followed by a 5-min break, after which the tests were repeated in the same order. Sputum expectorated during autogenic drainage was quantified as dry weight and correlated with change between post- and pre-measurements (Δ). Paired t test or Wilcoxon signed-rank tests were used to compare pre- and post-autogenic drainage measurement outcomes. A P value of ≤.05 was considered as statistically significant. Twenty-four subjects were studied (18 females, median age [range]: 65 [21-81] y). Mean ± SD LCI significantly improved after autogenic drainage (10.88 ± 2.62 vs 10.53 ± 2.35, P = .042). However, only 20% of subjects with mucus hyperproduction during autogenic drainage had a ΔLCI that exceeded measurement variability. The percent of predicted slow vital capacity (SVC%) also slightly improved (88.7 ± 19.3% vs 90 ± 19.1%, P = .02). ΔLCI was inversely related to dry sputum weight (r = -.48, P = .02) and ΔSVC% (r = -.64, P = .001). ΔSVC% also correlated with dry sputum weight (r = 0.46, P = .02). In adults with non-cystic fibrosis bronchiectasis and mucus hypersecretion, autogenic drainage improved ventilation inhomogeneity. LCI change may be the result of the maximum recruited lung volume and the amount of cleared mucus secretion. (ClinicalTrials.gov registration NCT02411981.).


Combination of Tevatron searches for the standard model Higgs boson in the W+W- decay mode.
We combine searches by the CDF and D0 Collaborations for a Higgs boson decaying to W+W-. The data correspond to an integrated total luminosity of 4.8 (CDF) and 5.4 (D0) fb(-1) of pp collisions at square root(s) = 1.96 TeV at the Fermilab Tevatron collider. No excess is observed above background expectation, and resulting limits on Higgs boson production exclude a standard model Higgs boson in the mass range 162-166 GeV at the 95% C.L.


Alterations of Diffusion Kurtosis and Neurite Density Measures in Deep Grey Matter and White Matter in Parkinson's Disease.
In Parkinson's disease (PD), pathological microstructural changes occur and such changes might be detected using diffusion magnetic resonance imaging (dMRI). However, it is unclear whether dMRI improves PD diagnosis or helps differentiating between phenotypes, such as postural instability gait difficulty (PIGD) and tremor dominant (TD) PD. We included 105 patients with PD and 44 healthy controls (HC), all of whom underwent dMRI as part of the prospective Swedish BioFINDER study. Diffusion kurtosis imaging (DKI) and neurite density imaging (NDI) analyses were performed using regions of interest in the basal ganglia, the thalamus, the pons and the midbrain as well as tractography of selected white matter tracts. In the putamen, the PD group showed increased mean diffusivity (MD) (p = .003), decreased fractional anisotropy (FA) (p = .001) and decreased mean kurtosis (MK), compared to HC (p = .024). High MD and a low MK in the putamen were associated with more severe motor and cognitive symptomatology (p < .05). Also, patients with PIGD exhibited increased MD in the putamen compared to the TD patients (p = .009). In the thalamus, MD was increased (p = .001) and FA was decreased (p = .032) in PD compared to HC. Increased MD and decreased FA correlated negatively with motor speed and balance (p < .05). In the superior longitudinal fasciculus (SLF), MD (p = .019) and fiso were increased in PD compared to HC (p = .03). These changes correlated negatively with motor speed (p < .002) and balance (p < .037). However, most of the observed changes in PD were also present in cases with either multiple system atrophy (n = 11) or progressive supranuclear palsy (n = 10). In conclusion, PD patients exhibit microstructural changes in the putamen, the thalamus, and the SLF, which are associated with worse disease severity. However, the dMRI changes are not sufficiently specific to improve the diagnostic work-up of PD. Longitudinal studies should evaluate whether dMRI measures can be used to track disease progression.


Reduced activity within the dorsal endogenous orienting of attention network to fearful expressions in youth with disruptive behavior disorders and psychopathic traits.
Using behavioral and blood oxygen level dependent (BOLD) response indices through functional magnetic resonance imaging (fMRI), the current study investigated whether youths with disruptive behavior disorders (conduct disorder and oppositional defiant disorder) plus psychopathic traits (DBD + PT) show aberrant sensitivity to eye gaze information generally and/or whether they show particular insensitivity to eye gaze information in the context of fearful expressions. The participants were 36 children and adolescents (ages 10-17 years); 17 had DBD + PT and 19 were healthy comparison subjects. Participants performed a spatial attention paradigm where spatial attention was cued by eye gaze in faces displaying fearful, angry, or neutral affect. Eye gaze sensitivity was indexed both behaviorally and as BOLD response. There were no group differences in behavioral response: both groups showed significantly faster responses if the target was in the congruent spatial direction indicated by eye gaze. Neither group showed a Congruence × Emotion interaction; neither group showed an advantage from the displayer's emotional expression behaviorally. However, the BOLD response revealed a significant Group × Congruence × Emotion interaction. The comparison youth showed increased activity within the dorsal endogenous orienting network (superior parietal lobule and inferior parietal sulcus) for fearful congruent relative to incongruent trials relative to the youth with DBD + PT. The results are discussed with reference to current models of DBD + PT and possible treatment innovations.


Randomised controlled trial of conditioning regimen for cord blood transplantation for adult myeloid malignancies comparing high-dose cytarabine/cyclophosphamide/total body irradiation with versus without G-CSF priming: G-CONCORD study protocol.
A better long-term quality of life after umbilical cord blood transplantation (CBT) is observed compared with transplants from other alternative donors, whereas graft failure and relapses after CBT are still major issues. To minimise graft failure and relapse after CBT, intensification of conditioning by the addition of high-dose cytosine arabinoside (CA) and concomitant continuous use of granulocyte-colony stimulating factor (G-CSF) are reported to convey a significantly better survival after CBT in some retrospective studies. To confirm the effect of G-CSF plus CA combination, in addition to the standard conditioning regimen, cyclophosphamide (CY)/total body irradiation (TBI), we design a randomised controlled study comparing CA/CY/TBI with versus without G-CSF priming (G-CSF combined conditioned cord blood transplantation [G-CONCORD] study). This is a multicentre, open-label, randomised phase III study that aimed to compare G-CSF+CA/CY/TBI as a conditioning regimen for CBT with CA/CY/TBI. Patients with acute myeloid leukaemia or myelodysplastic syndrome, aged 16-55 years, are eligible. The target sample size is 160 and the registration period is 4 years. The primary endpoint is the 2-year disease-free survival rate after CBT. The secondary endpoints are overall survival, relapse, non-relapse mortality, acute and chronic graft-versus-host disease, engraftment rate, time to neutrophil recovery, short-term adverse events, incidence of infections and causes of death.This study employs a single one-to-one web-based randomisation between the with-G-CSF versus without-G-CSF groups after patient registration. Combination of high-dose CA and CY/TBI in both groups is used for conditioning. The study protocol was approved by the central review board, Nagoya University Certified Review Board, after the enforcement of the Clinical Trials Act in Japan. The manuscripts presenting data from this study will be submitted for publication in quality peer-reviewed medical journals. Study findings will be disseminated via presentations at national/international conferences and peer-reviewed journals. UMIN000029947 and jRCTs041180059.


Predicting functional decline in behavioural variant frontotemporal dementia.
Behavioural variant frontotemporal dementia is characterized by a change in comportment. It is associated with considerable functional decline over the course of the illness albeit with sometimes dramatic variability among patients. It is unknown whether any baseline features, or combination of features, could predict rate of functional decline in behavioural variant frontotemporal dementia. The aim of this study was to investigate the effects of different baseline clinical, neuropsychological, neuropsychiatric, genetic and anatomic predictors on the rate of functional decline as measured by the Clinical Dementia Rating Sum of Boxes scale. We identified 86 subjects with behavioural variant frontotemporal dementia that had multiple serial Clinical Dementia Rating Sum of Boxes assessments (mean 4, range 2-18). Atlas-based parcellation was used to generate volumes for specific regions of interest at baseline. Volumes were utilized to classify subjects into different anatomical subtypes using the advanced statistical technique of cluster analysis and were assessed as predictor variables. Composite scores were generated for the neuropsychological domains of executive, language, memory and visuospatial function. Behaviours from the brief questionnaire form of the Neuropsychiatric Inventory were assessed. Linear mixed-effects regression modelling was used to determine which baseline features predict rate of future functional decline. Rates of functional decline differed across the anatomical subtypes of behavioural variant frontotemporal dementia, with faster rates observed in the frontal dominant and frontotemporal subtypes. In addition, subjects with poorer performance on neuropsychological tests of executive, language and visuospatial function, less disinhibition, agitation/aggression and night-time behaviours at presentation, and smaller medial, lateral and orbital frontal lobe volumes showed faster rates of decline. In many instances, the effect of the predictor variables observed across all subjects was also preserved within anatomical subtypes. Furthermore, some of the predictor variables improved our prediction of rate of functional decline after anatomical subtype was taken into account. In particular, age at onset was a highly significant predictor but only after adjusting for subtype. We also found that although some predictor variables, for example gender, Mini-Mental State Examination score, and apathy/indifference, did not affect the rate of functional decline; these variables were associated with the actual Clinical Dementia Rating Sum of Boxes score estimated for any given time-point. These findings suggest that in behavioural variant frontotemporal dementia, rate of functional decline is driven by the combination of anatomical pattern of atrophy, age at onset, and neuropsychiatric characteristics of the subject at baseline.


Systematic review and network meta-analysis of interventions for fibromyalgia: a protocol.
Fibromyalgia is associated with substantial socioeconomic loss and, despite considerable research including numerous randomized controlled trials (RCTs) and systematic reviews, there exists uncertainty regarding what treatments are effective. No review has evaluated all interventional studies for fibromyalgia, which limits attempts to make inferences regarding the relative effectiveness of treatments. We will conduct a network meta-analysis of all RCTs evaluating therapies for fibromyalgia to determine which therapies show evidence of effectiveness, and the relative effectiveness of these treatments. We will acquire eligible studies through a systematic search of CINAHL, EMBASE, MEDLINE, AMED, HealthSTAR, PsychINFO, PapersFirst, ProceedingsFirst, and the Cochrane Central Registry of Controlled Trials. Eligible studies will randomly allocate patients presenting with fibromyalgia or a related condition to an intervention or a control. Teams of reviewers will, independently and in duplicate, screen titles and abstracts and complete full text reviews to determine eligibility, and subsequently perform data abstraction and assess risk of bias of eligible trials. We will conduct meta-analyses to establish the effect of all reported therapies on patient-important outcomes when possible. To assess relative effects of treatments, we will construct a random effects model within the Bayesian framework using Markov chain Monte Carlo methods. Our review will be the first to evaluate all treatments for fibromyalgia, provide relative effectiveness of treatments, and prioritize patient-important outcomes with a focus on functional gains. Our review will facilitate evidence-based management of patients with fibromyalgia, identify key areas for future research, and provide a framework for conducting large systematic reviews involving indirect comparisons.


Seasonal Distribution of Bemisia tabaci (Hemiptera: Aleyrodidae) MEAM1 Species and Impact on Incidence of Begomoviral Diseases in Baja California Sur.
For more than four decades, the presence of the whitefly Bemisia tabaci Gennadius complex as a pest and transmitter of begomoviral diseases has been one of the most important phytopathological events in cultivated species worldwide. In addition, the number of whitefly species, as well as the viruses they transmit, has been increasing over time. In the state of Baja California Sur (BCS), Mexico, the diversity of B. tabaci has been delimited to MEAM1 and NW species, affecting mainly tomato, pepper, and squash. However, the relationship of these species with the dispersion of the begomoviruses previously detected in the study area is still unknown. In a 5-yr study (2012-2016), these species of whiteflies and begomoviruses were identified. Moreover, the recurrence, seasonal distribution, and impact they have on the spread of the begomoviral diseases were assessed. The identification of whiteflies was done targeting the mtCOI by PCR-DNA barcoding assay. For begomoviruses identification, a set of degenerate and specific primers targeting the IR region and CP gene were used. To determine seasonal abundance, monitoring was performed every 15 d by means of yellow traps. The MEAM1 species in all localities was observed with the highest peak population (>10 whiteflies/trap) from March to April. The guidelines for naming begomovirus species for the International Committee on Taxonomy of Viruses (ICTV) establish that the names when they are preceded by the acronym the whole name is in lowercase, not italicized (e.g. bean golden mosaic virus (BGMV)); when the name goes alone without the acronym then its capitalizes the first letter (e.g. Bean golden mosaic virus) and when these are referred to in a taxonomic sense they are italicized and the first letter is capitalized (e.g. Bean golden mosaic virus). This study provides details of the distribution and occurrence of MEAM1 species and diversity of begomoviruses that could be useful in disease management in BCS and worldwide.


Environmental and economic sustainability of poultry litter gasification for electricity and heat generation.
This work aims to assess the environmental and economic sustainability of poultry litter gasification for heat and electricity generation. The results are compared with gasification of two other biomass feedstocks (Miscanthus and waste wood) and energy from fossil fuels. The findings suggest that poultry litter gasification can lead to significant reductions in 14 out of 16 impacts considered in the study in comparison with fossil-fuel alternatives. Compared to combined heat and power (CHP) from natural gas, most impacts from gasification of the litter are lower by more than 90%, including global warming potential. However, human toxicity and depletion of minerals are 25% and three times higher, respectively. Energy from poultry litter also has lower impacts than from waste woodchips and Miscanthus across all the categories, except for acidification. Owing to high capital costs, the unsubsidised cost of generating heat and electricity from poultry litter is similar to that of natural gas CHP but significantly cheaper than from other fossil-fuel alternatives. However, with the current subsidies in the UK, the payback time for poultry litter gasification is 13.5 years. It is estimated that 4.55 Mt of poultry litter is currently available in the UK, 2.73 Mt of which is suitable for conversion to energy. If this waste is utilised in gasification plants, it could potentially provide 0.6% of electricity and heat in the UK and save 1.7 Mt of GHG per year, equivalent to around 0.4% of UK's GHG emissions. However, the successful uptake of this technology will depend on a future reduction in capital costs.


A theoretical study on the dynamics of light harvesting in the dimeric photosystem II core complex: regulation and robustness of energy transfer pathways.
Here we present our theoretical investigations into the light reaction in the dimeric photosystem II (PSII) core complex. An effective model for excitation energy transfer (EET) and primary charge separation (CS) in the PSII core complex was developed, with model parameters constructed based on molecular dynamics (MD) simulation data. Compared to experimental results, we demonstrated that this model faithfully reproduces the absorption spectra of the RC and core light-harvesting complexes (CP43 and CP47) as well as the full EET dynamics among the chromophores in the PSII core complex. We then applied master equation simulations and network analysis to investigate detailed EET plus CS dynamics in the system, allowing us to identify key EET pathways and produce a coarse-grained cluster model for the light reaction in the dimeric PSII core complex. We show that non-equilibrium energy transfer channels play important roles in the efficient light harvesting process and that multiple EET pathways exist between subunits of PSII to ensure the robustness of light harvesting in the system. Furthermore, we revealed that inter-monomer energy transfer dominated by the coupling between the two CLA625 molecules enables efficient energy exchange between two CP47s in the dimeric PSII core complex, which leads to significant energy pooling in the CP47 domain during the light reaction. Our study provides a blueprint for the design of light harvesting in the PSII core and show that a structure-based approach using molecular dynamics simulations and quantum chemistry calculations can be effectively utilized to elucidate the dynamics of light harvesting in complex photosynthetic systems.


Synthesis and display of dynamic holographic 3D scenes with real-world objects.
A 3D scene is synthesized combining multiple optically recorded digital holograms of different objects. The novel idea consists of compositing moving 3D objects in a dynamic 3D scene using a process that is analogous to stop-motion video. However in this case the movie has the exciting attribute that it can be displayed and observed in 3D. We show that 3D dynamic scenes can be projected as an alternative to complicated and heavy computations needed to generate realistic-looking computer generated holograms. The key tool for creating the dynamic action is based on a new concept that consists of a spatial, adaptive transformation of digital holograms of real-world objects allowing full control in the manipulation of the object's position and size in a 3D volume with very high depth-of-focus. A pilot experiment to evaluate how viewers perceive depth in a conventional single-view display of the dynamic 3D scene has been performed.


Men increase contributions to a public good when under sexual competition.
Why humans cooperate in large groups and with non-kin remains a puzzle for researchers across the natural and social sciences. Investigating whether cooperation is sexually selected could contribute to an understanding of the evolution of human cooperation. Competition for access to mates could indeed select for cooperation. Using controlled laboratory experiments, we analyse whether and how the sex composition of a social environment, testosterone level, and relationship status affect contributions to a public good. The results show that variation in sex composition alters the amount of money that single men (but not men in a couple or women) contribute to a public good. Notably, in line with the competitive helping hypothesis, awareness of the presence of a woman leads to larger contributions by single men, most likely by triggering their competitiveness to be the most cooperative man in the group. However, we find no link between basal testosterone level and cooperativeness. We argue that men, notably single men, adopt cooperative behaviours as a signalling strategy in the context of mate choice and hence that cooperation is partly sexually selected. Our findings highlight the need to consider sexual selection as an additional mechanism for cooperation.


The European Reference Network for Rare Neurological Diseases.
While rare diseases (RDs) are by definition of low prevalence, the total number of patients suffering from an RD is high, and the majority of them have neurologic manifestations, involving central, peripheral nerve, and muscle. In 2017, 24 European Reference Networks (ERNs), each focusing on a specific group of rare or low-prevalence complex diseases, were formed to improve the care for patients with an RD. One major aim is to have "the knowledge travel instead of the patient," which has been put into practice by the implementation of the Clinical Patient Management System (CPMS) that enables clinicians to perform pan-European virtual consultations. The European Reference Network for Rare Neurological Diseases (ERN-RND) provides an infrastructure for knowledge sharing and care coordination for patients affected by a rare neurological disease (RND) involving the most common central nervous system pathological conditions. It covers the following disease groups: (i) Cerebellar Ataxias and Hereditary Spastic Paraplegias; (ii) Huntington's disease and Other Choreas; (iii) Frontotemporal dementia; (iv) Dystonia, (non-epileptic) paroxysmal disorders, and Neurodegeneration with Brain Iron Accumulation; (v) Leukoencephalopathies; and (vi) Atypical Parkinsonian Syndromes. At the moment, it unites 32 expert centers and 10 affiliated partners in 21 European countries, as well as patient representatives, but will soon cover nearly all countries of the European Union as a result of the ongoing expansion process. Disease expert groups developed and consented on diagnostic flowcharts and disease scales to assess the different aspects of RNDs. ERN-RND has started to discuss diagnostically unclear patients in the CPMS, is one of four ERNs that serve as foundation of Solve-RD, and has established an RND training and education program. The network will facilitate trial readiness through the establishment of an ERN-RND registry with a minimal data of all patients seen at the ERN-RND centers, thus providing a unique overview of existing genotype-based cohorts. The overall aim of the ERNs is to improve access for patients with RDs to quality diagnosis, care, and treatment. Based on this objective, ERNs are monitored by the European Commission on a regular basis to provide transparency and reassurance to the RD community and the general public.


The benefits of including clinical factors in rectal normal tissue complication probability modeling after radiotherapy for prostate cancer.
To study the impact of clinical predisposing factors on rectal normal tissue complication probability modeling using the updated results of the Dutch prostate dose-escalation trial. Toxicity data of 512 patients (conformally treated to 68 Gy [n = 284] and 78 Gy [n = 228]) with complete follow-up at 3 years after radiotherapy were studied. Scored end points were rectal bleeding, high stool frequency, and fecal incontinence. Two traditional dose-based models (Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) and a logistic model were fitted using a maximum likelihood approach. Furthermore, these model fits were improved by including the most significant clinical factors. The area under the receiver operating characteristic curve (AUC) was used to compare the discriminating ability of all fits. Including clinical factors significantly increased the predictive power of the models for all end points. In the optimal LKB, RS, and logistic models for rectal bleeding and fecal incontinence, the first significant (p = 0.011-0.013) clinical factor was "previous abdominal surgery." As second significant (p = 0.012-0.016) factor, "cardiac history" was included in all three rectal bleeding fits, whereas including "diabetes" was significant (p = 0.039-0.048) in fecal incontinence modeling but only in the LKB and logistic models. High stool frequency fits only benefitted significantly (p = 0.003-0.006) from the inclusion of the baseline toxicity score. For all models rectal bleeding fits had the highest AUC (0.77) where it was 0.63 and 0.68 for high stool frequency and fecal incontinence, respectively. LKB and logistic model fits resulted in similar values for the volume parameter. The steepness parameter was somewhat higher in the logistic model, also resulting in a slightly lower D(50). Anal wall DVHs were used for fecal incontinence, whereas anorectal wall dose best described the other two endpoints. Comparable prediction models were obtained with LKB, RS, and logistic NTCP models. Including clinical factors improved the predictive power of all models significantly.


Donald Munro Lecture 2003. Neurogenic bladder: past, present, and future.
The foundation of the management of neurogenic bladder can be attributed to a pioneer in spinal cord injury medicine. Dr. Donald Munro, a neurosurgeon, who also had experience in urologic surgery, established the first Spinal Cord Injury Service of 10 beds in the Boston City hospital in the 1930s. He later became adviser to the US Army and the Veterans Administration (VA). On his recommendation, paraplegic centers were created in US army hospitals and later in the VA hospitals from 1943 to 1945. This article reviews the evolution of the management of neurogenic bladder in patients with spinal cord injuries from the past century to the present. The role of urodynamics in defining neurologic lesions is critical to the appropriate management of the voiding dysfunction. Key advances, such as the diagnosis of detrusor sphincter dyssynergia (DSD), recognition of its association with autonomic dysreflexia, and its definitive management, have been emphasized. The role of transrectal linear array sonography using a rectal probe was found useful for defining bladder outlet dysfunction during urodynamics. It also helped to recognize secondary bladder neck obstruction and diagnose false passages in the urethra. Clean technique intermittent catheterization (IC) was evaluated and recommended. In about 28% patients with DSD that led to secondary bladder neck obstruction, a consequence of IC was reported. Transurethral laser sphincterotomy (TURS) was first reported by me in 1991, and later, durable 7-year follow-up results were reported in 78% of the first 99 patients. We reported a surgical technique to lengthen the penis. We also reported the long-term success with semirigid implants in 92% of patients with SCI. This technique helped maintain external condom drainage on a small phallus and improved the sex life of patients, as well as their quality of life. The author's pertinent areas of interest in the past one-half century were aimed at recognizing specific urologic problems associated with neurologic impairment. Management was aimed at preventive care, early recognition, and timely management to reduce secondary complications and enhance quality of life.


Identification of the myostatin locus (MSTN) as having a major effect on optimum racing distance in the Thoroughbred horse in the USA.
One hundred and eighty-nine Thoroughbred horses that had won Graded Stakes races in North America were genotyped with the Illumina Equine SNP50 bead chip. Association tests using PLINK to determine whether any SNPs were associated with optimum racing distance (7 furlongs and under compared to 8-10 furlongs) identified a locus on ECA18 that was statistically significant (-log 10 EMP2=1.63) at the genome-wide level following permutation analysis (10,000 permutations). Bioinformatic analysis revealed that the two ECA18 SNPs with the highest statistical significance spanned the MSTN (myostatin) locus. Mutations in myostatin in several mammalian species have been associated with increased muscling, with a preferential increase in fast glycolytic type IIB fibres, which would increase power potential. Thoroughbred horses that race over sprint distances, which are 5-7 furlongs, are often characterized by impressive hind quarter musculature, strongly suggesting that the association observed between the ECA18 SNPs and optimum race distance is mediated through MSTN.


Parent and peer communication effects on AIDS-related behavior among U.S. high school students.
Data from a 1989 national probability sample of 8,098 high school students in the United States indicate that young people's discussions about the human immunodeficiency virus (HIV) with parents and with peers are highly correlated and have opposite effects on behavior. Students who discussed HIV with their parents were less likely than those who did not to have had multiple sex partners, to have had unprotected sexual intercourse and to have ever injected drugs; on the other hand, students who discussed HIV with their peers were more likely than those who did not to have had multiple partners and to have had unprotected sexual intercourse. Subgroup analyses show that young women were influenced more by HIV discussions with parents, while young men were influenced more by discussions with peers; some communication effects differed by race and ethnicity. Students who received HIV instruction in school were more likely to have talked about HIV with both parents and peers.


The association between physiological and behavioral pain measures in 0- to 3-year-old infants after major surgery.
To estimate the association between behavioral and physiological pain measures and to identify determinants predicting the level of association, the COMFORT 'behavior' scale, heart rate (HR), mean arterial pressure (MAP), and the variability of HR and MAP (HRV and MAPV) were assessed every 3 hours after major abdominal or thoracic surgery. Subjects were 204 infants aged 0-3 years. The within-subject correlations, using the repeated measures, were 0.37, 0.44, 0.48, and 0.49 for COMFORT 'behavior' with HRV, HR, MAP, and MAPV, respectively. Neonates had lower behavior-physiology correlations than the older infants, due to low pain scores. Pain characteristics significantly predicted the COMFORT 'behavior'-HR/MAP correlations, suggesting that the behavior-physiology correlations increase with increasing pain. The behavior-physiology correlations were not greatly affected by physical condition. These data demonstrate large interindividual differences in behavior-physiology correlations after major surgery in 0- to 3-year-old infants. These differences should be further explored in future research.


What would Batman do? Self-distancing improves executive function in young children.
This experimental research assessed the influence of graded levels of self-distancing - psychological distancing from one's egocentric perspective - on executive function (EF) in young children. Three- (n = 48) and 5-year-old (n = 48) children were randomly assigned to one of four manipulations of distance from the self (from proximal to distal: self-immersed, control, third person, and exemplar) on a comprehensive measure of EF. Performance increased as a function of self-distancing across age groups. Follow-up analyses indicated that 5-year-olds were driving this effect. They showed significant improvements in EF with increased distance from the self, outperforming controls both when taking a third person perspective on the self and when taking the perspective of an exemplar other (e.g., Batman) through role play. Three-year-olds, however, did not show increased EF performance as a function of greater distance from the self. Preliminary results suggest that developments in theory of mind might contribute to these age-related differences in efficacy. These findings speak to the importance of psychological distancing in the expression of conscious control over thought and action from a young age and suggest a promising new avenue for early EF intervention.


English speech acquisition in 3- to 5-year-old children learning Russian and English.
English speech acquisition in Russian-English (RE) bilingual children was investigated, exploring the effects of Russian phonetic and phonological properties on English single-word productions. Russian has more complex consonants and clusters and a smaller vowel inventory than English. One hundred thirty-seven single-word samples were phonetically transcribed from 14 RE and 28 English-only (E) children, ages 3;3 (years;months) to 5;7. Language and age differences were compared descriptively for phonetic inventories. Multivariate analyses compared phoneme accuracy and error rates between the two language groups. RE children produced Russian-influenced phones in English, including palatalized consonants and trills, and demonstrated significantly higher rates of trill substitution, final devoicing, and vowel errors than E children, suggesting Russian language effects on English. RE and E children did not differ in their overall production complexity, with similar final consonant deletion and cluster reduction error rates, similar phonetic inventories by age, and similar levels of phonetic complexity. Both older language groups were more accurate than the younger language groups. We observed effects of Russian on English speech acquisition; however, there were similarities between the RE and E children that have not been reported in previous studies of speech acquisition in bilingual children. These findings underscore the importance of knowing the phonological properties of both languages of a bilingual child in assessment.


Mitigating effects of antioxidant properties of black berry juice on sodium fluoride induced hepatotoxicity and oxidative stress in rats.
Fluorosis is a serious public health problem in many parts of the world. As in the case of many chronic degenerative diseases, increased production of reactive oxygen species has been considered to play an important role, even in the pathogenesis of chronic fluoride toxicity. Black berry is closely linked to its protective properties against free radical attack. Therefore, the aim of this study was to demonstrate the role of black berry juice (BBJ) in decreasing the hepatotoxicity and oxidative stress of sodium fluoride (NaF). Results showed that NaF caused elevation in liver TBARS and nitric oxide (NO), and reduction in superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (TAC) and glutathione (GSH). Plasma transaminases (AST and ALT), creatine kinase (CK), lactate dehydrogenase (LDH), total lipids (TL), cholesterol, triglycerides (TG), and low density lipoprotein-cholesterol (LDL-c) were increased, while high density lipoprotein-cholesterol (HDL-c) was decreased. On the other hand, BBJ reduced NaF-induced TBARS, NO, TL, cholesterol, TG, LDL-c, AST, ALT, CK and LD. Moreover, it ameliorated NaF-induced decrease in SOD, CAT, GSH, TAC and HDL-c. Therefore, the present results revealed that BBJ has a protective effect against NaF-induced hepatotoxicity by antagonizing the free radicals generation and enhancement of the antioxidant defence mechanisms.


CD16+NKG2Ahigh Natural Killer Cells Infiltrate Breast Cancer-Draining Lymph Nodes.
Tumor-draining lymph nodes (TD-LNs) are the first site of metastasis of breast cancer. Natural killer (NK) cells that infiltrate TD-LNs [including noninvaded (NI) or metastatic (M)-LNs from breast cancer patients] and NK cells from healthy donor (HD)-LNs were characterized, and their phenotype analyzed by flow cytometry. Low percentages of tumor cells invaded M-LNs, and these cells expressed ULBP2 and HLA class I molecules. Although NK cells from paired NI and M-LNs were similar, they expressed different markers compared with HD-LN NK cells. Compared with HD-LNs, TD-LN NK cells expressed activating DNAM-1, NKG2C and inhibitory NKG2A receptors, and exhibited elevated CXCR3 expression. CD16, NKG2A, and NKp46 expression were shown to be increased in stage IIIA breast cancer patients. TD-LNs contained a large proportion of activated CD56brightCD16+ NK cells with high expression of NKG2A. We also showed that a subset of LN NK cells expressed PD-1, expression of which was correlated with NKp30 and NKG2C expression. LN NK cell activation status was evaluated by degranulation potential and lytic capacity toward breast cancer cells. NK cells from TD-LNs degranulated after coculture with breast cancer cell lines. Cytokine-activated TD-LN NK cells exerted greater lysis of breast cancer cell lines than HD-LN NK cells and preferentially lysed the HLA class Ilow MCF-7 breast cancer cell line. TD-LNs from breast cancer patients, thus, contained activated lytic NK cells. The expression of inhibitory receptor NKG2A and checkpoint PD-1 by NK cells infiltrating breast cancer-draining LNs supports their potential as targets for immunotherapies using anti-NKG2A and/or anti-PD-1.


Reduced anterior and posterior cingulate gray matter in borderline personality disorder.
Structural abnormalities in prefrontal and cingulate gyrus regions-important in affective processing, impulse control and cognition may contribute to the psychopathology of borderline personality disorder (BPD). Previous MRI studies examining volume have reported that compared with healthy controls, BPD patients have decreases in right anterior cingulate, no differences in dorsolateral prefrontal cortex, and mixed findings for prefrontal cortex. We extended this investigation by examining gray and white matter volume of frontal and cingulate gyrus Brodmann areas (BAs) in a large group of patients and healthy controls. MRI scans were acquired in 50 BPD patients (n = 13 with comorbid diagnosis of BPD and Schizotypal Personality Disorder (SPD) and n = 37 without SPD) and 50 healthy controls, and gray/white matter volume in cingulate gyrus and frontal lobe BAs were assessed. Normal BPD and BPD subgroup comparisons were conducted. Compared with controls, BPD patients showed reduced gray matter volume in BA 24 and 31 of the cingulate. BPD patients without comorbid SPD had isolated gray matter volume loss in BA 24, but were spared for BA 31 in contrast to BPD patients with SPD. There were no group differences in whole cingulate or frontal lobe volume. The finding of more pervasive cingulate shrinkage in the patients with BPD and SPD comorbidity resembles recent observations with the same methods in patients with schizophrenia. The pattern of reduced anterior and posterior cingulate gray matter volume in BPD patients, particularly those comorbid for SPD is consistent with the affective and attentional deficits observed in these personality disorders.


Retrospective validation of whole genome sequencing-enhanced surveillance of listeriosis in Europe, 2010 to 2015.
Background and aimThe trend in reported case counts of invasive Listeria monocytogenes (Lm), a potentially severe food-borne disease, has been increasing since 2008. In 2015, 2,224 cases were reported in the European Union/European Economic Area (EU/EEA). We aimed to validate the microbiological and epidemiological aspects of an envisaged EU/EEA-wide surveillance system enhanced by routine whole genome sequencing (WGS). Methods: WGS and core genome multilocus sequence typing (cgMLST) were performed on isolates from 2,726 cases from 27 EU/EEA countries from 2010-15. Results: Quality controls for contamination, mixed Lm cultures and sequence quality classified nearly all isolates with a minimum average coverage of the genome of 55x as acceptable for analysis. Assessment of the cgMLST variation between six different pipelines revealed slightly less variation associated with assembly-based analysis compared to reads-based analysis. Epidemiological concordance, based on 152 isolates from 19 confirmed outbreaks and a cluster cutoff of seven allelic differences, was good (sensitivity > 95% for two cgMLST schemes of 1,748 and 1,701 loci each; PPV 58‒68%). The proportion of sporadic cases was slightly below 50%. Of remaining isolates, around one third were in clusters involving more than one country, often spanning several years. Detection of multi-country clusters was on average several months earlier when pooling the data at EU/EEA level, compared with first detection at national level. Conclusions: These findings provide a good basis for comprehensive EU/EEA-wide, WGS-enhanced surveillance of listeriosis. Time limits should not be used for hypothesis generation during outbreak investigations, but should be for analytical studies.


Subthalamotomy in parkinsonian monkeys. Behavioural and biochemical analysis.
Nineteen Macaca fascicularis monkeys were divided into four different groups: Group A (n = 3), control; Group B (n = 3), monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); Group C (n = 8), animals treated with MPTP in which the subthalamic nucleus (STN) was unilaterally lesioned by kainic acid injection; in Group D (n = 5), the STN was lesioned prior to MPTP administration. Subthalamotomy resulted in a bilateral improvement of tremor, spontaneous activity, bradykinesia (evaluated by a manual motor test) and freezing in Group C. All these monkeys developed hemichorea contralateral to the lesion. The improvement was maintained and the hemichorea continued until death. The monkeys in group D showed severe hemiballism which persisted throughout MPTP administration and developed parkinsonian signs mainly on the side ipsilateral to the lesion. Analysis of the in situ hybridization of the mRNA coding for glutamic acid decarboxylase (GAD) of MPTP monkeys showed a significant increase in the mean density of silver grains over every labelled neuron in the globus pallidum lateralis (56.8% over control) as well as the globus pallidus medialis (GPM) (45.7% over control) and the substantia nigra reticulata (SNR) (35.8% over control). No significant change was observed in the thalamic nucleus reticularis. Subthalamotomy (Groups C and D) produced a significant reduction in mRNA GAD expression on the side of the lesion in the GPM and the SNR (34% and 42.3%, respectively) with respect to the ipsilateral (non-lesioned) side and also when compared with parkinsonian monkeys. These results confirm and expand, at the cellular level, the paramount role of STN hyperactivity in the pathophysiology of parkinsonism. The therapeutic consequences of these findings for surgical treatment of Parkinson's disease are discussed.


Doctors' and nurses' perceptions of military pre-hospital emergency care - When training becomes reality.
The aim of this study was to identify physicians' and nurses' perceptions of military pre-hospital emergency care before and after an international mission. A qualitative empirical study with a phenomenographic approach was used. The results after pre-deployment training can be categorised as (1) learning about military medicine and (2) taking care of the casualty. The results after an international mission can be categorised as (1) collaborating with others, (2) providing general health care and (3) improving competence in military medicine. These results indicate that the training should be developed in order to optimise pre-deployment training for physicians and nurses. This may result in increased safety for the provider of care, while at the same time minimising suffering and enhancing the possibility of survival of the injured.


In Situ Deactivation of Catechol-Containing Adhesive Using Electrochemistry.
Marine mussels secret catechol-containing adhesive proteins that enable these organisms to bind to various surfaces underwater. Synthetic mimics of these proteins have been created to function as adhesives and coatings for a wide range of applications. Here, we demonstrated the use of in situ electrical field stimulation to deactivate the adhesive property of catechol-containing adhesive that is in direct contact with a surface. Johnson-Kendall-Roberts (JKR) contact mechanics test was performed using a titanium (Ti) sphere in the presence of a pH 7.5 aqueous buffer. The Ti sphere also served as a conductive electrode for applying electricity to the adhesive, while a platinum (Pt) wire served as the counter electrode. Work of adhesion (Wadh) decreased with increased levels of applied voltage and current, exposure time to the applied electricity, and salt concentration of the interfacial buffer. Application of 9 V for 1 min completely deactivated the adhesive. UV-vis diffuse reflectance spectra and tracking of catechol oxidation byproduct, hydrogen peroxide, confirmed that catechol was oxidized as a result of applied electricity. Contact mechanics testing further confirmed that the Young's modulus of the adhesive increased by nearly 4 folds at the interface as a result of oxidative cross-linking, even though the modulus of the bulk of the adhesive was unaffected by applied electricity. The accumulation of hydroxyl ions near the cathode increased the local solution pH, which promoted oxidation-induced cross-linking of catechol and subsequently decreased its adhesive property. Tuning adhesive properties through in situ electrochemical oxidation provides on-demand control over the adhesive, which will potentially add another dimension in designing synthetic mimics of mussel adhesive proteins.


Action of green tea catechin on bone metabolic disorder in chronic cadmium-poisoned rats.
The purpose of this study was to investigate the effects of green tea catechin on bone metabolic disorders and its mechanism in chronic cadmium-poisoned rats. Sprague-Dawley male rats weighing 100+/-10 g were randomly assigned to one control group and three cadmium-poisoned groups. The cadmium groups included a catechin free diet (Cd-0C) group, a 0.25% catechin diet (Cd-0.25C) group and a 0.5% catechin diet (Cd-0.5C) group according to their respective levels of catechin supplement. After 20 weeks, the deoxypyridinoline and crosslink values measured in urine were significantly increased in the Cd-0C group. Cadmium intoxication seemed to lead to an increase in bone resorption. In the catechin supplemented group (Cd-0.5C group), these urinary bone resorption marks, were decreased. The serum osteocalcin content in the cadmium-poisoned group was significantly increased as compared with the control group. In the catechin supplemented group serum osteocalcin content values were lower than the control group. The cadmium-intoxicated group (Cd-0C group), had lower bone mineral density than the control group (total body, vertebra, pelvis, tibia and femur). The catechin supplement increased bone mineral density to about the same as the control group. Bone mineral content showed a similar trend to total bone mineral density. Therefore, the bone mineral content of the Cd-0C group at the 20th week was significantly lower than the control group. The catechin supplemented group (Cd-0.5C group) was about the same as the control group. The cause of decreasing bone mineral density and bone mineral content by cadmium poisoning was due to the fast bone turnover rate, where bone resorption occurred at a higher rate than bone formation. The green tea catechin aided in normalizing bone metabolic disorders in bone mineral density, bone mineral content and bone calcium content caused by chronic cadmium intoxication.


Antiinflammatory Activity of Hot Water Infusion of Nyctanthes arbo-tristis Flowers.
In Sri Lankan ethnomedicate it is claimed the flowers of Nyctanthes arbo-tristis is effective in the treatment of inflammatory conditions but this has not been scientifically validated. This experiment was carried to investigate the antinflammatory potential of hot water infusion of Nyctanthes arbo-tristis flowers. Oral antiinflammatory activity of hot water infusion of Nyctanthes arbo-tristis flowers (concentrations: 3.75, 7.5, 12.5 and 18.75 mg/kg) was assessed in rats using both acute (carrageenan-induced paw oedema assay) and chronic (formaldehyde induced-paw oedema and cotton pellet-granuloma tests) inflammatory models. In an attempt to investigate its mode of action, antihistamine activity (by wheal test), inhibition of prostaglandin synthesis (by enteropooling test), inhibition of Tumor necrosis factorα secretion (using human mononuclear cells), and suppression of vascular permeability (acetic acid-induced vascular permeability test) and cytotoxicity (Evans blue test) were assessed. In the carrageenan-induced paw oedema test, hot water infusion simultaneously suppressed both initial and late stages of inflammation in an inversely dose related manner. Hot water infusion also inhibited paw oedema in formalin and cotton pellet granuloma tests. In addition, this infusion exhibited marked anti histamine activity, prostaglandin synthesis inhibition and suppression of vascular permeability. These findings scientifically support the traditional use of Nyctanthes arbo-tristis flowers in treatment of inflammatory conditions.


Hematologic Toxicity of Concurrent Administration of Radium-223 and Next-generation Antiandrogen Therapies.
Radium-223 is a first-in-class radiopharmaceutical recently approved for the treatment of castration-resistant prostate cancer in patients with symptomatic bone metastases. Initial studies investigating Radium-223 primarily used nonsteroidal first-generation antiandrogens. Since that time, newer antiandrogen therapies have demonstrated improved survival in patients with castration-resistant prostate cancer. It has been suggested that the rational combination of these newly approved agents with Radium-223 may lead to improved response rates and clinical outcomes. Currently, there is lack of information regarding the safety of concurrent administration of these agents with radiopharmaceuticals. Here, we report on hematologic toxicity findings from our institution in patients receiving concurrent Radium-223 and next-generation antiandrogen therapies with either enzalutamide or abiraterone. In a retrospective study, we analyzed patients who received Radium-223 as part of an early-access trial, and following FDA approval in May 2013, patients receiving Radium-223 as part of standard care. Radium-223 was given at standard dosing of 50 kBq/kg each month for 6 total cycles. Complete blood counts were performed before treatment monthly and following each injection. Blood counts from patients receiving Radium alone and concurrently with next-generation antiandrogens were compared. To date, 25 total patients were analyzed, with a median of 5 monthly doses received per patient. Fourteen patients received concurrent therapy during monthly Radium-223 with either enzalutamide (n=8) or abiraterone (n=6). Six patients expired due to disease progression. Two patients discontinued treatment due to grade 3 myelosuppression. For patients receiving either Radium alone and with concurrent next-generation antiandrogen therapy, there did not appear to be any statistically significant differences between initial and nadir blood counts. Mean change from initial neutrophil count to nadir was 1.9×10/L in patients receiving Radium alone, versus 2.3×10/L in patients receiving concurrent therapy (P=0.77). Mean change from initial hemoglobin value to nadir was 1.5 g/L in patients receiving Radium alone, versus 1.8 g/L in patients receiving concurrent therapy (P=0.31). Mean change from initial platelet count to nadir was 52.3×10 cells/L in patients receiving Radium alone versus 70.6×10 cells/L in patients receiving concurrent therapy (P=0.39). Individual blood counts for each measured laboratory are included in the supplemental data. PSA was stable or decreased in 22% of patients receiving Radium alone versus 35% of patients receiving combination treatment (P=0.24). Concurrent administration of Radium-223 and next-generation antiandrogen therapies appears to be well tolerated with similar toxicities to standard administration of Radium-223 alone. This particular cohort of patients represents a high-risk, heavily pretreated group of patients with advanced metastatic disease and significant marrow burden. Despite these risk factors, hematologic toxicity was modest and was in the range expected for this risk group based on previous trials. To date, this is the first study investigating the toxicity of combination treatment. Further studies investigating the safety and efficacy of combination treatments are warranted.


Ptbp1 and Exosc9 knockdowns trigger skin stability defects through different pathways.
In humans, genetic diseases affecting skin integrity (genodermatoses) are generally caused by mutations in a small number of genes that encode structural components of the dermal-epidermal junctions. In this article, we first show that inactivation of both exosc9, which encodes a component of the RNA exosome, and ptbp1, which encodes an RNA-binding protein abundant in Xenopus embryonic skin, impairs embryonic Xenopus skin development, with the appearance of dorsal blisters along the anterior part of the fin. However, histological and electron microscopy analyses revealed that the two phenotypes are distinct. Exosc9 morphants are characterized by an increase in the apical surface of the goblet cells, loss of adhesion between the sensorial and peridermal layers, and a decrease in the number of ciliated cells within the blisters. Ptbp1 morphants are characterized by an altered goblet cell morphology. Gene expression profiling by deep RNA sequencing showed that the expression of epidermal and genodermatosis-related genes is also differentially affected in the two morphants, indicating that alterations in post-transcriptional regulations can lead to skin developmental defects through different routes. Therefore, the developing larval epidermis of Xenopus will prove to be a useful model for dissecting the post-transcriptional regulatory network involved in skin development and stability with significant implications for human diseases.


Gender schema theory and sex role inventories: some conceptual and psychometric considerations.
In this study we assessed whether the Bem Sex Role Inventory (BSRI) and the PRF ANDRO are appropriate for investigations of gender schema theory (Bem, 1981a). Because these instruments were developed for entirely different theoretical purposes, it is important to empirically examine the validity of these measures for investigating the construct of gender schema. On the basis of the propositions of gender schema theory, we made several predictions about the psychometric properties that should be exhibited by a valid measure of this construct. Responses to the PRF ANDRO and the BSRI were factor analyzed separately for sex-typed and non-sex-typed groups. Results show consistent and theoretically predictable differences in the factor solutions of these two groups. The sex-typed or gender-schematic group obtained bipolar factors, with masculine items loading with one sign, whereas feminine items loaded with the other sign on each factor. Also, sex of subject loaded highly on almost every factor for this group. The non-sex-typed group, however, obtained few such distinctly dichotomous factors, and sex of subject loaded only on the weaker factors. Results are interpreted as providing support for the construct validity of at least the BSRI and the PRF ANDRO for use in researching the implications of this approach.


Registration accuracy and quality of real-life images.
A common registration problem for the application of consumer device is to align all the acquired image sequences into a complete scene. Image alignment requires a registration algorithm that will compensate as much as possible for geometric variability among images. However, images captured views from a real scene usually produce different distortions. Some are derived from the optic characteristics of image sensors, and others are caused by the specific scenes and objects. An image registration algorithm considering the perspective projection is proposed for the application of consumer devices in this study. It exploits a multiresolution wavelet-based method to extract significant features. An analytic differential approach is then proposed to achieve fast convergence of point matching. Finally, the registration accuracy is further refined to obtain subpixel precision by a feature-based modified Levenberg-Marquardt method. Due to its feature-based and nonlinear characteristic, it converges considerably faster than most other methods. In addition, vignette compensation and color difference adjustment are also performed to further improve the quality of registration results. The performance of the proposed method is evaluated by testing the synthetic and real images acquired by a hand-held digital still camera and in comparison with two registration techniques in terms of the squared sum of intensity differences (SSD) and correlation coefficient (CC). The results indicate that the proposed method is promising in registration accuracy and quality, which are statistically significantly better than other two approaches.


Experimental evidence of a new class of massless fermions.
The discovery of graphene with its massless fermions established a new branch of nanomaterials in which linear bands can be realized. It has been predicted that beside Dirac fermions revealing isotropic character and observed in a number of two-dimensional materials, another class of massless fermions can also be found: strongly anisotropic fortune teller-like states which form planes instead of cones in the electronic structure. Here, we demonstrate that such distinct electronic structures exist and can be found in a surface layer of silicon.


Comparison of outcomes for supine vs. prone position ERCP: a systematic review and meta-analysis.
Background While endoscopic retrograde cholangiopancreatography (ERCP) is usually performed in the prone position, some studies have advocated for ERCP in the supine position. Studies comparing the technical success and safety outcomes have shown variable results. We performed a systematic review and meta-analysis of studies reporting the comparison between the two positions for ERCP outcomes. Methods We conducted a search of electronic databases and conference proceedings including PubMed, EMBASE, and Web of Science databases (from inception through October 2016) to identify studies that reported the comparison of technical success and safety outcomes between supine and prone ERCP. The primary outcome was to estimate the pooled rates of technical success. The secondary outcome was to estimate the risks of complications, such as cardiopulmonary and post-ERCP pancreatitis (PEP). Results Six studies reporting on 309 supine and 1415 prone ERCPs were identified. The pooled technical success rates for completion of ERCP in supine and prone positions were 89.1 % (95 %CI = 80.9 - 94.0) and 95.6 % (95 %CI = 91.5 - 97.7), respectively. The pooled rates for complications (cardiopulmonary and PEP) in the supine position were 37.5 % (95 %CI = 19.1 - 60.3) and 3.5 % (95 %CI = 1.6 - 7.3), respectively. The pooled rates for complications (cardiopulmonary and PEP) in the prone position were 41.0 % (95 %CI = 20.9 - 64.8) and 3.9 % (95 %CI = 2.4 - 6.4), respectively. The mean time required for the procedure was 30 minutes and 29.8 minutes for supine and prone positions, respectively. Substantial heterogeneity was noted in the analysis. Conclusion Prone ERCPs have a higher technical success rate with a slightly lower mean duration but a higher number of adverse events. The decision with regard to patient position should be made after evaluating the overall clinical scenario.


In-MOFs based on amide functionalised flexible linkers.
Two new amide functionalised metal-organic frameworks, In(OH)CSA and In(OH)PDG, were synthesized using two flexible linkers, N-(4-carboxyphenyl)succinamic acid (CSA) and N,N'-(1,4-phenylenedicarbonyl)diglycine (PDG), respectively. Both structures consist of corner-sharing {InO4(OH)2} octahedra in the form of trans indium hydroxide chains, which are interconnected by the dicarboxylate linkers to form stacked 2-dimensional layers. The different symmetries and configurations of the flexible and rigid features on the linkers results in different supramolecular interactions dominating between linkers, resulting in different shaped pores and functional group orientation. In(OH)CSA lacks hydrogen bonding between linkers, which results in close packing between the layers and very small solvent accessible pores running perpendicular to the plane of the layers. In(OH)PDG exhibits strong intra- and interlayer hydrogen bonding, which prevents the layers from close packing and results in larger cylindrical pores running parallel to the indium hydroxide chains, producing a total accessible volume of 25% of the unit cell volume.


Associations between weight status and liking scores for sweet, salt and fat according to the gender in adults (The Nutrinet-Santé study).
As taste preferences may be associated with obesity, the present study investigated whether obese subjects presented heightened liking for the sensations of sweet, salt and fat. Liking scores were determined by a questionnaire including 83 items on liking for sweet or fatty foods, and the preferred extent of seasoning with salt, sweet or fat. Data from 46909 adults included in the French web-based observational cohort of the Nutrinet-Santé study were collected and weighted according to the national population census. Relationships between liking scores and body mass index (BMI) as categorical or linear explanatory variable were assessed separately by gender using covariance and linear regression analyses, adjusted for age, education level, living area, smoking and alcohol. Overall liking scores for salt and fat were linearly positively linked to BMI in men and women (P≤0.001) and were higher in obese than in normal-weight individuals. The score difference between BMI categories was greater in women for fat liking only. For sweet liking, results differed between gender and compounding factors. Liking for added sugar and sweet foods was positively linked to BMI in women unlike in men; liking for natural sweetness was negatively linked to BMI in both genders. This study demonstrates that the relationship between liking and BMI differs according to the gender in its magnitude for fat and in its nature for sweet, unlike that for salt. Liking for sweet and fat may be linked to overconsumption of the corresponding foods, especially in women. This warrants further investigation.


Characterization of the killer cell generated in the autologous mixed leukocyte reaction.
Cytotoxic cells are produced in an autologous mixed leukocyte reaction (AMLR). At 1 wk in culture the AMLR killers are mainly IgG Fc- cells and can kill autologous lymphoblastoid cell lines and Raji and Daudi targets that are usually resistant to natural killer cell (NK) lysis. To define the phenotype of these cells, we have used complement (C')-mediated lysis with monoclonal antibodies (MAb). AMLR killer activity was virtually eliminated by treatment with C' and 9.6 or 4F2, but the cytotoxic cells did not express NK-specific antigens, OKM1 and Leu-7, nor cytolytic T lymphocyte-specific antigens, 9.3 and OKT8. None of the 10 MAb used could significantly block cytotoxicity at the final concentration of 1.5 mcg/ml which is generally sufficient to inhibit CTL. The majority of cells at 1 wk in AMLR cultures stained with T cell activation antigens Ia and 4F2; AMLR killing was proportional to the percentage of 4F2+ cells but unrelated to the expression of Ia antigen.


A genome-wide association study of optic disc parameters.
The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc area and the vertical cup-disc ratio (VCDR). Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA) data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p = 6.72x10(-19)) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p = 2.67x10(-33)) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p = 6.15x10(-11)) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p = 2.93x10(-10)) within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N = 3,612), and the TwinsUK cohort (N = 843). Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant), and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origin.


Frequency doubling by active in vivo motility of mechanosensory neurons in the mosquito ear.
Across vertebrate and invertebrate species, nonlinear active mechanisms are employed to increase the sensitivity and acuity of hearing. In mosquitoes, the antennal hearing organs are known to use active force feedback to enhance auditory acuity to female generated sounds. This sophisticated form of signal processing involves active nonlinear events that are proposed to rely on the motile properties of mechanoreceptor neurons. The fundamental physical mechanism for active auditory mechanics is theorized to rely on a synchronization of motile neurons, with a characteristic frequency doubling of the force generated by an ensemble of motile mechanoreceptors. There is however no direct biomechanical evidence at the mechanoreceptor level, hindering further understanding of the fundamental mechanisms of sensitive hearing. Here, using in situ and in vivo atomic force microscopy, we measure and characterize the mechanical response of mechanosensory neuron units during forced oscillations of the hearing organ. Mechanoreceptor responses exhibit the hallmark of nonlinear feedback for force generation, with movements at twice the stimulus frequency, associated with auditory amplification. Simultaneous electrophysiological recordings exhibit similar response features, notably a frequency doubling of the firing rate. This evidence points to the nature of the mechanism, whereby active hearing in mosquitoes emerges from the double-frequency response of the auditory neurons. These results open up the opportunity to directly investigate active cellular mechanics in auditory systems, and they also reveal a pathway to study the nanoscale biomechanics and its dynamics of cells beyond the sense of hearing.


[Drugs active against retroviruses].
Major advances in understanding the pathogenesis and treatment of human immunodeficiency virus (HIV) infection have been made recently. The reverse transcriptase and protease enzymes of HIV are currently the targets of antiretroviral therapy. Nucleoside analogues were the first class of antiretroviral drugs which demonstrated antiviral activity in treating patients. More recently protease inhibitors have provided new approaches in the treatment of HIV infection, with encouraging trial results in patients receiving combined therapy. This review presents their mechanisms of activity and patterns of resistance. Apart from these main drug groups many new compounds are under development.


Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the AleCardio randomized clinical trial.
No therapy directed against diabetes has been shown to unequivocally reduce the excess risk of cardiovascular complications. Aleglitazar is a dual agonist of peroxisome proliferator-activated receptors with insulin-sensitizing and glucose-lowering actions and favorable effects on lipid profiles. To determine whether the addition of aleglitazar to standard medical therapy reduces cardiovascular morbidity and mortality among patients with type 2 diabetes mellitus and a recent acute coronary syndrome (ACS). AleCardio was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial conducted in 720 hospitals in 26 countries throughout North America, Latin America, Europe, and Asia-Pacific regions. The enrollment of 7226 patients hospitalized for ACS (myocardial infarction or unstable angina) with type 2 diabetes occurred between February 2010 and May 2012; treatment was planned to continue until patients were followed-up for at least 2.5 years and 950 primary end point events were positively adjudicated. Randomized in a 1:1 ratio to receive aleglitazar 150 µg or placebo daily. The primary efficacy end point was time to cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Principal safety end points were hospitalization due to heart failure and changes in renal function. The trial was terminated on July 2, 2013, after a median follow-up of 104 weeks, upon recommendation of the data and safety monitoring board due to futility for efficacy at an unplanned interim analysis and increased rates of safety end points. A total of 3.1% of patients were lost to follow-up and 3.2% of patients withdrew consent. The primary end point occurred in 344 patients (9.5%) in the aleglitazar group and 360 patients (10.0%) in the placebo group (hazard ratio, 0.96 [95% CI, 0.83-1.11]; P = .57). Rates of serious adverse events, including heart failure (3.4% for aleglitazar vs 2.8% for placebo, P = .14), gastrointestinal hemorrhages (2.4% for aleglitazar vs 1.7% for placebo, P = .03), and renal dysfunction (7.4% for aleglitazar vs 2.7% for placebo, P < .001) were increased. Among patients with type 2 diabetes and recent ACS, use of aleglitazar did not reduce the risk of cardiovascular outcomes. These findings do not support the use of aleglitazar in this setting with a goal of reducing cardiovascular risk. clinicaltrials.gov Identifier: NCT01042769.