Acute inhalation of hypertonic saline does not improve mucociliary clearance in all children with cystic fibrosis

<p>Abstract</p> <p>Background</p> <p>Little is known of how mucociliary clearance (MCC) in children with cystic fibrosis (CF) and normal pulmonary function compares with healthy adults, or how an acute inhalation of 7% hypertonic saline (HS) aerosol affects MCC in these same children.</p> <p>Methods</p> <p>We compared MCC in 12 children with CF and normal pulmonary function after an acute inhalation of 0.12% saline (placebo), or HS, admixed with the radioisotope ^{99 m}technetium sulfur colloid in a double-blind, randomized, cross-over study. Mucociliary clearance on the placebo day in the children was also compared to MCC in 10 healthy, non-CF adults. Mucociliary clearance was quantified over a 90 min period, using gamma scintigraphy, and is reported as MCC at 60 min (MCC60) and 90 min (MCC90).</p> <p>Results</p> <p>Median [interquartile range] MCC60 and MCC90 in the children on the placebo visit were 15.4 [12.4-24.5]% and 19.3 [17.3-27.8%]%, respectively, which were similar to the adults with 17.8 [6.4-28.7]% and 29.6 [16.1-43.5]%, respectively. There was no significant improvement in MCC60 (2.2 [-6.2-11.8]%) or MCC90 (2.3 [-1.2-10.5]%) with HS, compared to placebo. In addition, 5/12 and 4/12 of the children showed a decrease in MCC60 and MCC90, respectively, after inhalation of HS. A <it>post hoc </it>subgroup analysis of the change in MCC90 after HS showed a significantly greater improvement in MCC in children with lower placebo MCC90 compared to those with higher placebo MCC90 (p = 0.045).</p> <p>Conclusions</p> <p>These data suggest that percent MCC varies significantly between children with CF lung disease and normal pulmonary functions, with some children demonstrating MCC values within the normal range and others showing MCC values that are below normal values. In addition, although MCC did not improve in all children after inhalation of HS, improvement did occur in children with relatively low MCC values after placebo. This finding suggests that acute inhalation of hypertonic saline may benefit a subset of children with low MCC values.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01293084">NCT01293084</a></p

New malonate-derived tetraglucoside detergents for membrane protein stability

Membrane proteins are widely studied in detergent micelles, a membrane-mimetic system formed by amphiphilic compounds. However, classical detergents have serious limitations in their utility, particularly for unstable proteins such as eukaryotic membrane proteins and membrane protein complexes, and thus, there is an unmet need for novel amphiphiles with enhanced ability to stabilize membrane proteins. Here, we developed a new class of malonate-derived detergents with four glucosides, designated malonate-derived tetra-glucosides (MTGs), and compared these new detergents with previously reported octyl glucose neopentyl glycol (OGNG) and n-dodecyl-β-d-maltoside (DDM). When tested with two G-protein coupled receptors (GPCRs) and three transporters, a couple of MTGs consistently conferred enhanced stability to all tested proteins compared to DDM and OGNG. As a result of favorable behaviors for a range of membrane proteins, these MTGs have substantial potential for membrane protein research. This study additionally provides a new detergent design principle based on the effect of a polar functional group (i.e., ether) on protein stability depending on its position in the detergent scaffold

Diastereomeric Cyclopentane-Based Maltosides (CPMs) as tools for membrane protein study

Amphiphilic agents, called detergents, are invaluable tools for studying membrane proteins. However, membrane proteins encapsulated by conventional head-to-tail detergents tend to denature or aggregate, necessitating the development of structurally distinct molecules with improved efficacy. Here, a novel class of diastereomeric detergents with a cyclopentane core unit, designated cyclopentane-based maltosides (CPMs), were prepared and evaluated for their ability to solubilize and stabilize several model membrane proteins. A couple of CPMs displayed enhanced behavior compared with the benchmark conventional detergent, n-dodecyl-β-d-maltoside (DDM), for all the tested membrane proteins including two G-protein-coupled receptors (GPCRs). Furthermore, CPM-C12 was notable for its ability to confer enhanced membrane protein stability compared with the previously developed conformationally rigid NBMs [J. Am. Chem. Soc.2017, 139, 3072] and LMNG. The effect of the individual CPMs on protein stability varied depending on both the detergent configuration (cis/trans) and alkyl chain length, allowing us draw conclusions on the detergent structure–property–efficacy relationship. Thus, this study not only provides novel detergent tools useful for membrane protein research but also reports on structural features of the detergents critical for detergent efficacy in stabilizing membrane proteins

Signal Detection on the Battlefield: Priming Self-Protection vs. Revenge-Mindedness Differentially Modulates the Detection of Enemies and Allies

Detecting signs that someone is a member of a hostile outgroup can depend on very subtle cues. How do ecology-relevant motivational states affect such detections? This research investigated the detection of briefly-presented enemy (versus friend) insignias after participants were primed to be self-protective or revenge-minded. Despite being told to ignore the objectively nondiagnostic cues of ethnicity (Arab vs. Western/European), gender, and facial expressions of the targets, both priming manipulations enhanced biases to see Arab males as enemies. They also reduced the ability to detect ingroup enemies, even when these faces displayed angry expressions. These motivations had very different effects on accuracy, however, with self-protection enhancing overall accuracy and revenge-mindedness reducing it. These methods demonstrate the importance of considering how signal detection tasks that occur in motivationally-charged environments depart from results obtained in conventionally motivationally-inert laboratory settings.National Institute of Mental Health (U.S.) (Grant MH64734)U.S. Army Research Institute for the Behavioral and Social Sciences (Grant W74V8H-05-K-0003)National Science Foundation (U.S.) (Grant BCS-0642873

Protocol for Work place adjusted Intelligent physical exercise reducing Musculoskeletal pain in Shoulder and neck (VIMS): a cluster randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Neck and shoulder complaints are common among employees in sedentary occupations characterized by intensive computer use. Specific strength training is a promising type of physical exercise for relieving neck and shoulder pain in office workers. However, the optimal combination of frequency and exercise duration, as well as the importance of exercise supervision, is unknown. The VIMS study investigates in a cluster randomized controlled design the effectiveness of different time wise combinations of specific strength training with identical accumulated volume, and the relevance of training supervision for safe and effective training.</p> <p>Methods/design</p> <p>A cluster randomized controlled trial of 20 weeks duration where employed office workers are randomized to 1 × 60 min, 3 × 20 min, 9 × 7 min per week of specific strength training with training supervision, to 3 × 20 min per week of specific strength training with a minimal amount of training supervision, or to a reference group without training. A questionnaire will be sent to 2000 employees in jobs characterized by intensive computer work. Employees with cardiovascular disease, trauma, hypertension, or serious chronic disease will be excluded. The main outcome measure is pain in the neck and shoulders at week 20.</p> <p>Trial Registration</p> <p>The trial is registered at ClinicalTrials.gov, number NCT01027390.</p

Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population

Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of that risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortia and population based resources, we find genetic links between ASDs and typical variation in social behavior and adaptive functioning. This finding is evidenced through both inherited and de novo variation, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in an ASD or other neuropsychiatric disorder diagnosis. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology

Relationship of obesity to physical activity, domestic activities, and sedentary behaviours: cross-sectional findings from a national cohort of over 70,000 Thai adults

Background: Patterns of physical activity (PA), domestic activity and sedentary behaviours are changing rapidly in Asia. Little is known about their relationship with obesity in this context. This study investigates in detail the relationship between obesity, physical activity, domestic activity and sedentary behaviours in a Thai population. Methods. 74,981 adult students aged 20-50 from all regions of Thailand attending the Sukhothai Thammathirat Open University in 2005-2006 completed a self-administered questionnaire, including providing appropriate self-reported data on height, weight and PA. We conducted cross-sectional analyses of the relationship between obesity, defined according to Asian criteria (Body Mass Index (BMI) 25), and measures of physical activity and sedentary behaviours (exercise-related PA; leisure-related computer use and television watching ("screen-time"); housework and gardening; and sitting-time) adjusted for age, sex, income and education and compared according to a range of personal characteristics. Results: Overall, 15.6% of participants were obese, with a substantially greater prevalence in men (22.4%) than women (9.9%). Inverse associations between being obese and total weekly sessions of exercise-related PA were observed in men, with a significantly weaker association seen in women (p(interaction) < 0.0001). Increasing obesity with increasing screen-time was seen in all population groups examined; there was an overall 18% (15-21%) increase in obesity with every two hours of additional daily screen-time. There were 33% (26-39%) and 33% (21-43%) reductions in the adjusted risk of being obese in men and women, respectively, reporting housework/gardening daily versus seldom or never. Exercise-related PA, screen-time and housework/gardening each had independent associations with obesity. Conclusions: Domestic activities and sedentary behaviours are important in relation to obesity in Thailand, independent of exercise-related physical activity. In this setting, programs to prevent and treat obesity through increasing general physical activity need to consider overall energy expenditure and address a wide range of low-intensity high-volume activities in order to be effective

Biomarkers for Severity of Spinal Cord Injury in the Cerebrospinal Fluid of Rats

One of the major challenges in management of spinal cord injury (SCI) is that the assessment of injury severity is often imprecise. Identification of reliable, easily quantifiable biomarkers that delineate the severity of the initial injury and that have prognostic value for the degree of functional recovery would significantly aid the clinician in the choice of potential treatments. To find such biomarkers we performed quantitative liquid chromatography-mass spectrometry (LC-MS/MS) analyses of cerebrospinal fluid (CSF) collected from rats 24 h after either a moderate or severe SCI. We identified a panel of 42 putative biomarkers of SCI, 10 of which represent potential biomarkers of SCI severity. Three of the candidate biomarkers, Ywhaz, Itih4, and Gpx3 were also validated by Western blot in a biological replicate of the injury. The putative biomarkers identified in this study may potentially be a valuable tool in the assessment of the extent of spinal cord damage