A phase 1 randomized, double-blind, placebo-controlled, crossover trial of DAS181 (Fludase®) in adult subjects with well-controlled asthma.
Influenza virus (IFV) infection is associated with increased morbidity and mortality in people with underlying lung disease. Treatment options for IFV are currently limited and antiviral resistance is a growing concern. DAS181, an inhaled antiviral with a unique mechanism of action, has shown promise in early clinical trials involving generally healthy human subjects. This study was undertaken to assess the safety and tolerability of DAS181 in individuals with underlying reactive airway disease. This was a randomized, double-blind, placebo-controlled, crossover phase 1 study of DAS181-F02. Dry particle inhaler administration of 10 mg was done on 3 consecutive days in ten adult volunteers with well-controlled asthma. The primary outcome was the frequency of adverse events (AEs), grade 1 or higher that occurred during each study period. There were 280 AEs among ten evaluable subjects (56.8 % active; 43.2 % placebo); 90.7 % were grade 1. No grade 3 or higher AEs occurred. A statistically significant association between exposure to DAS181 and experiencing any AE, a grade 1 AE, or a grade 2 AE was not detected. Overall, the majority of AEs were classified as possibly related (35.7 %), unlikely related (38.9 %), or unrelated (15.4 %) to study drug administration. However, there was a statistically significant association between exposure to DAS181 and experiencing a definitely or probably related AE. Respiratory effects, including dyspnea, dry cough, and chest discomfort related to respirations, accounted for all of the definitely related AEs and one of the most common probably related AEs. DAS181 was safe in this small study of otherwise healthy subjects with well-controlled asthma. However, the generalizability of these results is limited by the small sample size and generally mild nature of the subjects' asthma at baseline. The increased association of respiratory events classified as probably or definitely related to DAS181 administration suggests caution may need to be employed when administering DAS181 to individuals with less stable reactive airway disease. Further investigation in a controlled setting of the safety and efficacy of DAS181 in a larger population of asthmatic subjects with varying disease activity is warranted. ClinicalTrials.gov NCT01113034 Trial Registration Date: April 27, 2010.


Wnt Pathway Stabilizes MeCP2 Protein to Repress PPAR-γ in Activation of Hepatic Stellate Cells.
PPAR-γ is essential for differentiation of hepatic stellate cells (HSC), and its loss due to epigenetic repression by methyl-CpG binding protein 2 (MeCP2) causes HSC myofibroblastic activation mediated in part via Wnt pathway, the key cellular event in liver fibrosis. Decreased miR-132 was previously proposed to promote MeCP2 protein translation for Ppar-γ repression in activated HSC (aHSC). The present study aimed to test this notion and to better understand the mechanisms of MeCP2 upregulation in aHSC. MeCP2 protein is increased on day 3 to 7 as HSC become activated in primary culture on plastic, but this is accompanied by increased but not reduced miR-132 or miR-212 which is also expected to target MeCP2 due to its similar sequence with miR-132. The levels of these mRNAs are decreased 40~50% in aHSCs isolated from experimental cholestatic liver fibrosis but increased 6-8 fold in aHSC from hepatotoxic liver fibrosis in rats. Suppression of either or both of miR132 and miR212 with specific anti-miRNA oligonucleotides (anti-oligo), does not affect MeCP2 protein levels in aHSCs. The Wnt antagonist FJ9 which inhibits HSC activation, increases miR-132/miR-212, reduces MeCP2 and its enrichment at 5' Ppar-γ promoter, and restores Ppar-γ expression but the anti-oligo do not prevent Ppar-γ upregulation. The pan-NADPH oxidase (NOX) inhibitor diphenyleneiodonium (DPI) also reduces both MeCP2 and stabilized non-(S33/S37/Thr41)-phospho β-catenin and reverts aHSC to quiescent cells but do not affect miR-132/miR-212 levels. Wnt antagonism with FJ9 increases MeCP2 protein degradation in cultured HSC, and FJ9-mediated loss of MeCP2 is rescued by leupeptin but not by proteasome and lysozome inhibitors. In conclusion, canonical Wnt pathway increases MeCP2 protein due to protein stability which in turn represses Ppar-γ and activates HSC.


Scoring of reflux symptoms associated with scleroderma and the usefulness of rabeprazole.
The high frequency of gastroesophageal reflux disease (GERD) as a complication of scleroderma (systemic sclerosis, SSc) calls for treatment with powerful acid suppressants such as proton pump inhibitors (PPI). The present study used a GERD-specific questionnaire to assess the symptoms of GERD in SSc patients, and examine the effectiveness of rabeprazole (RPZ) for treating the symptoms of GERD. The Frequency Scale for the Symptoms of GERD (FSSG), a medical questionnaire developed in Japan for evaluating GERD, and the Visual Analogue Scale (VAS) were used to evaluate GERD symptoms and the degree of pain, respectively, in 151 SSc subjects. These tools were also used to assess the effect of 8 weeks' treatment with the PPI RPZ (10 mg/day). Data on age and gender, and FSSG and VAS scores before treatment and after 4 and 8 weeks' RPZ treatment, were available for 84 subjects. The mean FSSG score was 13.9+/-9.7 before treatment, 8.3+/-8.1 after 4 weeks of treatment, and 7.0+/-7.0 after 8 weeks of treatment; the score reduction was significant (p<0.001) indicating the effectiveness of RPZ in improving subjective GERD symptoms. The VAS scores revealed a significant improvement in pain after both 4 and 8 weeks compared with baseline scores. Six subjects experienced adverse effects and five discontinued the analysis during the period. Administration of RPZ 10 mg/day is effective for the control of the symptoms of GERD associated with SSc. In addition to assessing the symptoms of GERD, the FSSG questionnaire can be used to evaluate the therapeutic effect of drugs.


Respiratory sinus arrhythmia in dogs. Effects of phasic afferents and chemostimulation.
We examined the hypothesis that respiratory sinus arrhythmia (RSA) is primarily a central phenomenon and thus that RSA is directly correlated with respiratory controller output. RSA was measured in nine anesthetized dogs, first during spontaneous breathing (SB) and then during constant flow ventilation (CFV), a technique whereby phasic chest wall movements and thoracic pressure swings are eliminated. Measurements of the heart rate and of the moving time averaged (MTA) phrenic neurogram during these two ventilatory modes were made during progressive hypercapnia and progressive hypoxia. RSA divided by the MTA phrenic amplitude (RSAa) showed a power-law relationship with both arterial carbon dioxide partial pressure (PaCO2) and oxygen saturation (SaO2), but with different exponents for different conditions. However, the power-law relation between RSAa and respiratory frequency had an exponent indistinguishable from -2 whether hypoxia or hypercapnia was the stimulus for increased respiratory drive, and during both CFV and spontaneous breathing (-1.9 +/- 0.4, hypoxia, SB; -1.8 +/- 0.7, hypoxia, CFV; -2.1 +/- 0.8, hypercapnia, SB; -1.9 +/- 0.7, hypercapnia, CFV). We conclude that respiratory sinus arrhythmia is centrally mediated and directly related to respiratory drive, and that changes in blood gases and phasic afferent signals affect RSA primarily by influencing respiratory drive.


Epicatechin limits renal injury by mitochondrial protection in cisplatin nephropathy.
Cisplatin nephropathy can be regarded as a mitochondrial disease. Intervention to halt such deleterious injury is under investigation. Recently, the flavanol (-)-epicatechin emerges as a novel compound to protect the cardiovascular system, owing in part to mitochondrial protection. Here, we have hypothesized that epicatechin prevents the progression of cisplatin-induced kidney injury by protecting mitochondria. Epicatechin was administered 8 h after cisplatin injury was induced in the mouse kidney. Cisplatin significantly induced renal dysfunction and tubular injury along with an increase in oxidative stress. Mitochondrial damages were also evident as a decrease in loss of mitochondrial mass with a reduction in the oxidative phosphorylation complexes and low levels of MnSOD. The renal damages and mitochondrial injuries were significantly prevented by epicatechin treatment. Consistent with these observations, an in vitro study using cultured mouse proximal tubular cells demonstrated that cisplatin-induced mitochondrial injury, as revealed by a decrease in mitochondrial succinate dehydrogenase activity, an induction of cytochrome c release, mitochondrial fragmentation, and a reduction in complex IV protein, was prevented by epicatechin. Such a protective effect of epicatechin might be attributed to decreased oxidative stress and reduced ERK activity. Finally, we confirmed that epicatechin did not perturb the anticancer effect of cisplatin in HeLa cells. In conclusion, epicatechin exhibits protective effects due in part to its ability to prevent the progression of mitochondrial injury in mouse cisplatin nephropathy. Epicatechin may be a novel option to treat renal disorders associated with mitochondrial dysfunction.


Global characterization of porcine intrauterine proteins during early pregnancy.
Total protein secreted in the intrauterine lumen increases between day 10 and 13 post-estrus in both cyclic and pregnant gilts. The objective of this experiment was to identify those intrauterine proteins whose secretion changes during this time period. Sixteen mature gilts were either mated (day 0) or remained cyclic and were slaughtered at either day 10 or day 13 (n = 4 per status by day). At slaughter, each uterine horn was flushed with 20 ml Minimal Essential Medium. Flushings were dialyzed extensively against distilled water. A 0.5 ml aliquot of each was lyophilized, subjected to two-dimensional PAGE, and protein spots were identified following Coomassie staining of each gel. Densitometry was used to compare relative amounts of each spot. After statistical analysis, spots that differed due to either day, status, or day by status interaction were excised and digested in-gel with trypsin. The resulting peptides were analyzed by tandem mass spectrometry (MS/MS). Using MS/MS data, protein identification for each spot was attempted. There were 280 matching spots, of which 132 were significantly (P < 0.05 or 0.01) affected by pregnancy status, day, or the day by status interaction. Most (73%) spots increased from day 10 to day 13 with no effect of pregnancy. Several spots were identified as proteases or their inhibitors. Others potentially modify glycolipids and/or glycoproteins. These results indicate that the concentrations of many proteins within the intrauterine environment during early pregnancy are independent of the conceptus and could play roles in regulating the endometrial or conceptus glycocalyx.


The Association of Intratumoral Germinal Centers with early-stage non-small cell lung cancer.
Lung cancers can display immune cell infiltration although the role of an adaptive immune response in disease pathogenesis is unknown. To investigate the possibility of a functional humoral response to the tumor, we surveyed histologic sections from non-small cell lung cancer (NSCLC) tumors for germinal centers (GCs) and assessed whether there was an association between the presence of GCs and tumor stage. Tumor sections from 91 patients with all stages of NSCLC were examined by a pathologist blinded to clinical data. GCs were identified by hematoxylin and eosin staining patterns and confirmed by immunohistochemical staining for B-cell markers, BCL-6 and CD21. The distribution of GCs within the tumor or the tumor margin was recorded. Statistical analysis was performed to evaluate the association between stage and presence of GCs. Thirty-five percent of all tumors evaluated contained GCs, and sections evaluated by immunohistochemistry showed positive staining for both B-cell markers. GCs were seen both within the tumor and the tumor margin, consistent with an immune response to antigen stimulation. Patients with stage I NSCLC had a higher prevalence of intratumoral GCs than patients with stages II to IV (Cochran-Armitage Trend Test p = 0.02011). There was no association of stage with GCs in the tumor margin. Intratumoral GCs are associated with early-stage NSCLC. Further characterization of intratumoral GCs may lead to new diagnostic and therapeutic strategies based on manipulation of the adaptive immune response.


The Economic Impact of Adult Hearing Loss: A Systematic Review.
Hearing impairment (HI) is highly prevalent in older adults and has been associated with adverse health outcomes. However, the overall economic impact of HI is not well described. The goal of this review was to summarize available data on all relevant costs associated with HI among adults. A literature search of PubMed, Embase, the Cochrane Library, CINAHL, and Scopus was conducted in August 2015. For this systematic review, data extraction and quality assessment were performed by 2 independent reviewers. Eligibility criteria for included studies were presence of quantitative estimation of economic impact or loss of productivity of patients with HI, full-text English-language access, and publication in an academic, peer-reviewed journal or government report prior to August 2015. This review follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. A meta-analysis was not performed owing to the studies' heterogeneity in outcomes measures, methodology, and study country. The initial literature search yielded 4595 total references. After 2043 duplicates were removed, 2552 publications underwent title and abstract review, yielding 59 articles for full-text review. After full-text review, 25 articles were included. Of the included articles, 8 incorporated measures of disability; 5 included direct estimates of medical expenditures; 8 included other cost estimates; and 7 were related to noise-induced or work-related HI. Estimates of the economic cost of lost productivity varied widely, from $1.8 to $194 billion in the United States. Excess medical costs resulting from HI ranged from $3.3 to $12.8 billion in the United States. Hearing loss is associated with billions of dollars of excess costs in the United States, but significant variance is seen between studies. A rigorous, comprehensive estimate of the economic impact of hearing loss is needed to help guide policy decisions around the management of hearing loss in adults.


The bipartite structure of the tRNA m1A58 methyltransferase from S. cerevisiae is conserved in humans.
Among all types of RNA, tRNA is unique given that it possesses the largest assortment and abundance of modified nucleosides. The methylation at N(1) of adenosine 58 is a conserved modification, occurring in bacterial, archaeal, and eukaryotic tRNAs. In the yeast Saccharomyces cerevisiae, the tRNA 1-methyladenosine 58 (m(1)A58) methyltransferase (Mtase) is a two-subunit enzyme encoded by the essential genes TRM6 (GCD10) and TRM61 (GCD14). While the significance of many tRNA modifications is poorly understood, methylation of A58 is known to be critical for maintaining the stability of initiator tRNA(Met) in yeast. Furthermore, all retroviruses utilize m(1)A58-containing tRNAs to prime reverse transcription, and it has been shown that the presence of m(1)A58 in human tRNA(3) (Lys) is needed for accurate termination of plus-strand strong-stop DNA synthesis during HIV-1 replication. In this study we have identified the human homologs of the yeast m(1)A Mtase through amino acid sequence identity and complementation of trm6 and trm61 mutant phenotypes. When coexpressed in yeast, human Trm6p and Trm61p restored the formation of m(1)A in tRNA, modifying both yeast initiator tRNA(Met) and human tRNA(3) (Lys). Stable hTrm6p/hTrm61p complexes purified from yeast maintained tRNA m(1)A Mtase activity in vitro. The human m(1)A Mtase complex also exhibited substrate specificity--modifying wild-type yeast tRNA(i) (Met) but not an A58U mutant. Therefore, the human tRNA m(1)A Mtase shares both functional and structural homology with the yeast tRNA m(1)A Mtase, possessing similar enzymatic activity as well as a conserved binary composition.


Use of computerized algorithm to identify individuals in need of testing for celiac disease.
Celiac disease (CD) is a lifelong immune-mediated disease with excess mortality. Early diagnosis is important to minimize disease symptoms, complications, and consumption of healthcare resources. Most patients remain undiagnosed. We developed two electronic medical record (EMR)-based algorithms to identify patients at high risk of CD and in need of CD screening. (I) Using natural language processing (NLP), we searched EMRs for 16 free text (and related) terms in 216 CD patients and 280 controls. (II) EMRs were also searched for ICD9 (International Classification of Disease) codes suggesting an increased risk of CD in 202 patients with CD and 524 controls. For each approach, we determined the optimal number of hits to be assigned as CD cases. To assess performance of these algorithms, sensitivity and specificity were calculated. Using two hits as the cut-off, the NLP algorithm identified 72.9% of all celiac patients (sensitivity), and ruled out CD in 89.9% of the controls (specificity). In a representative US population of individuals without a prior celiac diagnosis (assuming that 0.6% had undiagnosed CD), this NLP algorithm could identify a group of individuals where 4.2% would have CD (positive predictive value). ICD9 code search using three hits as the cut-off had a sensitivity of 17.1% and a specificity of 88.5% (positive predictive value was 0.9%). This study shows that computerized EMR-based algorithms can help identify patients at high risk of CD. NLP-based techniques demonstrate higher sensitivity and positive predictive values than algorithms based on ICD9 code searches.


Coarse-grained molecular dynamics simulations of the sphere to rod transition in surfactant micelles.
Surfactant molecules self-assemble in aqueous solutions to form various micellar structures such as spheres, rods, or lamellae. Although phase transitions in surfactant solutions have been studied experimentally, their molecular mechanisms are still not well understood. In this work, we show that molecular dynamics (MD) simulations using the coarse-grained (CG) MARTINI force field and explicit CG solvent, validated against atomistic MD studies, can accurately represent micellar assemblies of cetyltrimethylammonium chloride (CTAC). The effect of salt on micellar structures is studied for aromatic anionic salts, e.g., sodium salicylate, and simple inorganic salts, e.g., sodium chloride. Above a threshold concentration, sodium salicylate induces a sphere to rod transition in the micelle. CG MD simulations are shown to capture the dynamics of this shape transition and support a mechanism based on the reduction in the micelle-water interfacial tension induced by the adsorption of the amphiphilic salicylate ions. At the threshold salt concentration, the interface is nearly saturated with adsorbed salicylate ions. Predictions of the effect of salt on the micelle structure in different CG solvent models, namely, single-site standard water and three-site polarizable water, show qualitative agreement. This suggests that phase transitions in aqueous micelle solutions could be investigated by using standard CG water models which allow for 3 orders of magnitude reduction in the computational time as compared to that required for atomistic MD simulations.


Plasma of pregnant and preeclamptic women activates monocytes in vitro.
The objective of the study was to test the hypothesis that factors circulating in the plasma of pregnant women and women with preeclampsia activate monocytes. Blood samples were taken from patients with early-onset severe preeclampsia (n = 9), healthy pregnant women (n = 9), and healthy nonpregnant women (n = 9). A monocytic cell line was incubated with the plasma for 4, 16, and 24 hours. After the incubation, reactive oxygen species (ROS) production and intercellular adhesion molecule (ICAM)-1 expression (protein and messenger ribonucleic acid) were measured. Plasma of both pregnant women and women with preeclampsia, as compared with plasma from nonpregnant women, increased the mean channel brightness (MCB) of ROS after 4 hours of incubation, whereas only plasma of pregnant women increased the percentage of cells producing ROS (after 4 and 24 hours of incubation). Plasma of pregnant women and women with preeclampsia up-regulated the percentage of ICAM-1-expressing cells after 4 hours and down-regulated the percentage of ICAM-1-expressing cells and MCB after 24 hours. Plasma of both pregnant women and women with preeclampsia activated monocytes in vitro.


Optical transmittance degradation in tapered fibers.
We investigated the cause of optical transmittance degradation in tapered fibers. Degradation commences immediately after fabrication and it eventually reduces the transmittance to almost zero. It is a major problem that limits applications of tapered fibers. We systematically investigated the effect of the dust-particle density and the humidity on the degradation dynamics. The results clearly show that the degradation is mostly due to dust particles and that it is not related to the humidity. In a dust free environment it is possible to preserve the transmittance with a degradation of less than the noise (±0.02) over 1 week.


The impact of user characteristics of smallholder farmers on user experiences with collaborative map applications.
In the future, farmers will have increasing opportunities to use collaborative smartphone applications for agricultural management. Geospatial information in combination with agricultural-relevant information is a great source of knowledge for farmers. Including maps in collaborative mobile agriculture applications benefits communication processes related to agricultural-relevant questions. Ensuring a positive user experience with map interfaces depends on their design. To develop design guidelines for map-oriented mobile agricultural applications, this study evaluates 24 different map design variations (varying in their elements and degrees of complexity) and characterizes their user experience with 72 coffee farmers as study participants. Our findings show that the most crucial factors for a positive user experience were restricted interactivity, simple tasks to conduct (selecting single point features), and a simplified base map style, highlighting relevant landmarks. Since our farmers consisted primarily of less-experienced smartphone and map users, our findings may also be helpful for users in general, sharing similar user characteristics. While empirical, in-situ studies pose many challenges, they provide relevant insights into the real use situation and user behavior of mobile map applications. Our findings help establish some basic principles for designing map adaptations, serving as a guideline for creating effective mapping applications, which adapt to the farmers' contextual factors. Based on our study results, we suggest future research for continuing conceptualizing principles of map design adaptation and support this effort through empirical, in-situ studies for relating contextual user factors to the adaptation behavior of map applications.


Is axillary dissection needed in node-positive breast cancer?
The standard of care in the management of the axilla for a woman with breast cancer was traditionally a level I and II axillary lymph node dissection (ALND). Since the pivotal studies in the mid-1990s, sentinel lymph node biopsy (SLNB) in breast carcinoma has come to replace ALND in women with clinically negative axillas. With the increased use of SLNB in women who present with breast carcinoma, the role of completion ALND for a positive sentinel lymph node has been challenged. We review the literature available and discuss future directions in identifying a subgroup who may avoid an ALND.


Use of beta blockers and the risk of death in hospitalised patients with acute exacerbations of COPD.
Cardiovascular disease is a major cause of death in patients with chronic obstructive pulmonary disease (COPD) and predicts hospitalisation for acute exacerbation, in-hospital death and post-discharge mortality. Although beta blockers improve cardiovascular outcomes, patients with COPD often do not receive them owing to concerns about possible adverse pulmonary effects. There are no published data about beta blocker use among inpatients with COPD exacerbations. A study was undertaken to identify factors associated with beta blocker use in this setting and to determine whether their use is associated with decreased in-hospital mortality. Administrative data from the University of Alabama Hospital were reviewed and patients admitted between October 1999 and September 2006 with an acute exacerbation of COPD as a primary diagnosis or as a secondary diagnosis with a primary diagnosis of acute respiratory failure were identified. Demographic data, co-morbidities and medication use were recorded and subjects receiving beta blockers were compared with those who did not. Multivariate regression analysis was performed to determine predictors of in-hospital death after controlling for known covariates and the propensity to receive beta blockers. 825 patients met the inclusion criteria. In-hospital mortality was 5.2%. Those receiving beta blockers (n = 142) were older and more frequently had cardiovascular disease than those who did not. In multivariate analysis adjusting for potential confounders including the propensity score, beta blocker use was associated with reduced mortality (OR = 0.39; 95% CI 0.14 to 0.99). Age, length of stay, number of prior exacerbations, the presence of respiratory failure, congestive heart failure, cerebrovascular disease or liver disease also predicted in-hospital mortality (p<0.05). The use of beta blockers by inpatients with exacerbations of COPD is well tolerated and may be associated with reduced mortality. The potential protective effect of beta blockers in this population warrants further study.


Daily stair climbing, disease susceptibility, and risk of atherosclerotic cardiovascular disease: A prospective cohort study.
The associations between intensity of stair climbing and atherosclerotic cardiovascular disease (ASCVD) and how these vary by underlying disease susceptibility are not fully understood. We aim to evaluate the intensity of stair climbing and risk of ASCVD types and whether these vary with the presence of ASCVD risk factors. This prospective study used data of 458,860 adult participants from the UK Biobank. Information about stair climbing, sociodemographic, and lifestyle factors was collected at baseline and a resurvey 5 years after baseline. ASCVD was defined as coronary artery disease (CAD), ischemic stroke (IS), or acute complications. Associations between flights of stair climbing and ASCVD were examined as hazard ratios (HRs) from Cox proportional hazards models. The modification role of disease susceptibility on such associations was assessed by analyses stratified by levels of genetic risk score (GRS), 10-year risks of ASCVD, and self-reported family history of ASCVD. During a median of 12.5 years of follow-up, 39,043 ASCVD, 30,718 CAD, and 10,521 IS cases were recorded. Compared with the reference group (reported climbing stairs 0 times/day at baseline), the multivariable-adjusted HRs for ASCVD were 0.97 (95% CI, 0.93-1.01), 0.84 (0.82-0.87), 0.78 (0.75-0.81), 0.77 (0.73-0.80) and 0.81 (0.77-0.85) for stair climbing of 1-5, 6-10, 11-15, 16-20 and ≥21 times/day, respectively. Comparable results were obtained for CAD and IS. When stratified by different disease susceptibility based on the GRS for CAD/IS, 10-year risk, and family history of ASCVD, the protection association of stair climbing was attenuated by increasing levels of disease susceptibility. Furthermore, compared with people who reported no stair climbing (<5 times/d) at two examinations, those who climbed stairs at baseline and then stopped at resurvey experienced a 32% higher risk of ASCVD (HR 1.32, 95% CI:1.06-1.65). Climbing more than five flights of stairs (approx 50 steps) daily was associated with a lower risk of ASCVD types independent of disease susceptibility. Participants who stopped stair climbing between baseline and resurvey had a higher risk of ASCVD compared with those who never climbed stairs.


The use of a wearable camera to capture and categorise the environmental and social context of self-identified eating episodes.
Research investigating the influence of the environmental and social factors on eating behaviours in free-living settings is limited. This study investigates the utility of using wearable camera images to assess the context of eating episodes. Adult participants (N = 40) wore a SenseCam wearable camera for 4 days (including 1 familiarisation day) over a 15-day period in free-living conditions, and had their diet assessed using three image-assisted multiple-pass 24-hour dietary recalls. The images of participants' eating episodes were analysed and annotated according to their environmental and social contexts; including eating location, external environment (indoor/outdoor), physical position, social interaction, and viewing media screens. Data for 107 days were used, with a total of 742 eating episodes considered for annotation. Twenty nine per cent (214/742) of the episodes could not be categorised due to absent images (12%, n = 85), dark/blurry images (8%, n = 58), camera not worn (7%, n = 54) and for mixed reasons (2%, n = 17). Most eating episodes were at home (59%) and indoors (91%). Meals at food retailers were 24.8 minutes longer (95% CI: 13.4 to 36.2) and were higher in energy (mean difference = 1196 kJ 95% CI: 242, 2149) than at home. Most episodes were seated at tables (27%) or sofas (26%), but eating standing (19%) or at desks (18%) were common. Social interaction was evident for 45% of episodes and media screens were viewed during 55% of episodes. Meals at home watching television were 3.1 minutes longer (95% CI: -0.6 to 6.7) and higher in energy intake than when no screen was viewed (543 kJ 95% CI: -32 to 1120). The environmental and social context that surrounds eating and dietary behaviours can be assessed using wearable camera images.


Inhaled budesonide in pulmonary sarcoidosis: a double-blind, placebo-controlled study. Dutch Study Group on Pulmonary Sarcoidosis.
In a double-blind, placebo-controlled study, we assessed the efficacy of inhaled budesonide on the course of newly diagnosed pulmonary sarcoidosis and whether budesonide treatment could postpone oral corticosteroid treatment. We evaluated: 1) symptoms; 2) chest radiography; 3) angiotensin-converting enzyme (ACE) in serum; and 4) lung function. Patients with histologically confirmed pulmonary sarcoidosis with chest radiographic stages I, II or III, and with an abnormal lung function (inspiratory vital capacity (IVC) < 79% of predicted or transfer factor of the lungs for carbon monoxide (TL,CO) < 77% pred) were included. Patients with radiographic stage II or III but with normal lung function were included when more than 20% of the total cell population in bronchoalveolar lavage fluid (BALF) was lymphocytes. Forty seven patients received placebo or budesonide (1.2 mg) once daily via a Nebuhaler for 6 months, followed by 6 months without treatment. Based on predetermined criteria, 11 patients were excluded during the blind treatment period as they needed oral prednisone: seven (28%) patients in the placebo group (n = 25) and four (18%) patients in the budesonide group (n = 22). Patient's Global Clinical Impression (GCI) score showed a significant difference in favour of budesonide. IVC showed a significant difference of 7.9% predicted between the two groups during the active treatment period. This difference persisted during follow-up, when the difference was 9.4% pred. TL,CO remained nearly unchanged over time, with no difference between the groups. Improvements in chest radiographic appearance and changes in serum ACE were similar for the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)


Long-term depression versus episodic major depression: results from the prospective Zurich study of a community sample.
Clinical studies have demonstrated a great clinical relevance of long-term depression (LTD). Our study aims to characterise LTD in comparison with episodic (non-chronic) major depressive episodes (MDE) on the basis of data from a community sample. The Zurich Cohort Study is a prospective study of young adults followed from age 20/21 to 40/41 with six interviews. The stratified sample consisted of two thirds high scorers and one third lower scorers on the Symptom Checklist-90 R (SCL-90-R). LTD was assessed from age 27/28 to 40/41 and defined as being symptomatic more days than not over 2 years plus the presence of work impairment. MDE and dysthymia were defined by DSM-III-R criteria. The cumulative incidence of LTD was 5.7%, and of episodic MDE 20.9%. In both groups we found a similar preponderance of women. LTD subjects reported disturbed memory, feelings of inferiority, hopelessness, fear of everyday tasks, fear of being alone and thoughts of dying significantly more often than subjects with episodic MDE. Subjects with LTD had an earlier age of onset. 82% of them were treated over lifetime for depression compared to 61% with MDE. LTD subjects were less often married, less often in fulltime employment, more often unemployed, and more often receiving social benefits. LTD was comorbid with cardiac and respiratory syndromes, and LTD subjects were more frequently treated for insomnia and pain. They suffered significantly more from social phobia and benzodiazepine abuse; there was also a statistical trend to greater comorbidity with panic attacks, agoraphobia, obsessive-compulsive syndrome, binge eating and neurasthenia. Somatic and psychological well-being were also reduced. LTD is common, clinically more serious than episodic MDE and highly comorbid. The sample is relatively small with an attrition rate of 38.5% over 20 years. The results cannot be generalised to persons over 40 years of age and may be dependent on the definition of LTD.


Do poor patients suffer from inaccurate diagnoses more than well-to-do patients? A randomized control trial.
Poor patients have greater morbidity and die up to 10 years earlier than patients who have higher socio-economic status. These findings are often attributed to differences in life-style between groups. The present study aimed at investigating the extent to which physicians contribute to the effect by providing relative poorer care, resulting in relative neglect in terms of time spent with a poor patient and more inaccurate diagnoses. A randomised experiment with 45 internal medicine residents. Doctors diagnosed 12 written clinical vignettes that were exactly the same except for the description of the patients' socio-economic status. Each participant diagnosed four of the vignettes in a poor-patient version, four in a rich-patient version, and four in a version that did not contain socio-economic markers, in a balanced within-subjects incomplete block design. Main measurements were: diagnostic accuracy scores and time spent on diagnosis. Mean diagnostic accuracy scores (range 0-1) did not significantly differ among the conditions of the experiment (for poor patients: 0.48; for rich patients: 0.52; for patients without socio-economic markers: 0.54; p > 0.05). While confronted with patients not presenting with socio-economic background information, the participants spent significantly less time-to-diagnosis ((for poor patients: 168 s; for rich patients: 176 s; for patients without socio-economic markers: 151 s; p < 0.01), however due to the fact that the former vignettes were shorter. There is no reason to believe that physicians are prejudiced against poor patients and therefore treat them differently from rich patients or patients without discernible socio-economic background.


Genome-Wide Association and Gene Co-expression Network Analyses Reveal Complex Genetics of Resistance to Goss's Wilt of Maize.
Goss's bacterial wilt and leaf blight is a disease of maize caused by the gram positive bacterium Clavibacter michiganensis subsp. nebraskensis (Cmn). First discovered in Nebraska, Goss's wilt has now spread to major maize growing states in the United States and three provinces in Canada. Previous studies conducted using elite maize inbred lines and their hybrids have shown that resistance to Goss's wilt is a quantitative trait. The objective of this study was to further our understanding of the genetic basis of resistance to Goss's wilt by using a combined approach of genome-wide association mapping and gene co-expression network analysis. Genome-wide association analysis was accomplished using a diversity panel consisting of 555 maize inbred lines and a set of 450 recombinant inbred lines (RILs) from three bi-parental mapping populations, providing the most comprehensive screening of Goss's wilt resistance to date. Three SNPs in the diversity panel and 10 SNPs in the combined dataset, including the diversity panel and RILs, were found to be significantly associated with Goss's wilt resistance. Each significant SNP explained 1-5% of the phenotypic variation for Goss's wilt (total of 8-11%). To augment the results of genome-wide association mapping and help identify candidate genes, a time course RNA sequencing experiment was conducted using resistant (N551) and susceptible (B14A) maize inbred lines. Gene co-expression network analysis of this time course experiment identified one module of 141 correlated genes that showed differential regulation in response to Cmn inoculations in both resistant and susceptible lines. SNPs inside and flanking these genes explained 13.3% of the phenotypic variation. Among 1,000 random samples of genes, only 8% of samples explained more phenotypic variance for Goss's wilt resistance than those implicated by the co-expression network analysis. While a statistically significant enrichment was not observed (P < 0.05), these results suggest a possible role for these genes in quantitative resistance at the field level and warrant more research on combining gene co-expression network analysis with quantitative genetic analyses to dissect complex disease resistance traits. The results of the GWAS and co-expression analysis both support the complex nature of resistance to this important disease of maize.


[Therapy of diaphyseal fractures of the leg in a district hospital].
During the period between 1987 and 1991 at the surgical department of the Trebíc hospital 136 casualties with closed diaphyseal fractures were treated. All patients were older than 18 years and monotraumas were involved. The patients were treated by immobilization by a classical high plaster bandage, functional plaster as recommended by Sarmient, extension treatment, miniosteosynthesis, osteosynthesis using a splint, intramedullary fixation as described by Küntscher and Simon-Enders-Weidner, or possibly by a combination of the mentioned methods. The author divides fractures of the leg into stable and unstable fractures and fracture with so-called urgently indicated osteosynthesis. The mean period of treatment with high plaster bandage was 31.7 weeks, functional plaster according to Sarmient 20.2 weeks, miniosteosynthesis with plaster fixation 25.5 weeks. When splints were used, the mean period of treatment was 30.5 weeks, in osteosynthesis according to Enders 20.6 weeks. The best results in stable fractures were achieved by functional plaster according to Sarmient, in unstable fractures and those with indicated osteosynthesis by using intramedullary fixation as described by Enders.


Comparison between conventional protective mechanical ventilation and high-frequency oscillatory ventilation associated with the prone position.
To compare the effects of high-frequency oscillatory ventilation and conventional protective mechanical ventilation associated with the prone position on oxygenation, histology and pulmonary oxidative damage in an experimental model of acute lung injury. Forty-five rabbits with tracheostomy and vascular access were underwent mechanical ventilation. Acute lung injury was induced by tracheal infusion of warm saline. Three experimental groups were formed: healthy animals + conventional protective mechanical ventilation, supine position (Control Group; n = 15); animals with acute lung injury + conventional protective mechanical ventilation, prone position (CMVG; n = 15); and animals with acute lung injury + high-frequency oscillatory ventilation, prone position (HFOG; n = 15). Ten minutes after the beginning of the specific ventilation of each group, arterial gasometry was collected, with this timepoint being called time zero, after which the animal was placed in prone position and remained in this position for 4 hours. Oxidative stress was evaluated by the total antioxidant performance assay. Pulmonary tissue injury was determined by histopathological score. The level of significance was 5%. Both groups with acute lung injury showed worsening of oxygenation after induction of injury compared with the Control Group. After 4 hours, there was a significant improvement in oxygenation in the HFOG group compared with CMVG. Analysis of total antioxidant performance in plasma showed greater protection in HFOG. HFOG had a lower histopathological lesion score in lung tissue than CMVG. High-frequency oscillatory ventilation, associated with prone position, improves oxygenation and attenuates oxidative damage and histopathological lung injury compared with conventional protective mechanical ventilation.


Intravaginal inoculation of rhesus macaques with cell-free simian immunodeficiency virus results in persistent or transient viremia.
The simian immunodeficiency virus (SIV)-rhesus macaque model of heterosexual human immunodeficiency virus transmission consists of atraumatic application of cell-free SIVmac onto the intact vaginal mucosa of mature female rhesus macaques. This procedure results in systemic infection, and eventually infected animals develop the clinical signs and pathologic changes of simian AIDS. To achieve 100% transmission with the virus stocks used to date, multiple intravaginal inoculations are required. The current titration study utilized two stocks of SIVmac and demonstrated that a single intravaginal dose of cell-free SIV can reliably produce infection in rhesus macaques. This study also demonstrated that some animals intravaginally inoculated with cell-free SIVmac develop transient viremia characterized by a limited ability to isolate virus from peripheral blood mononuclear cells and lymph node mononuclear cells and no seroconversion to SIV antigen. SIV could be isolated from the peripheral lymph nodes of transiently viremic animals only during periods of viremia and not at times when SIV was not detected in circulating mononuclear cells. Thus, peripheral lymphoid tissues were not reservoirs of infection in the transiently viremic animals. Taken together, these results suggest either that the SIV infection was cleared in the transiently viremic animals or that SIV infection is limited to a compartment of the genital mucosal immune system that cannot be assessed by monitoring SIV infection in peripheral blood mononuclear cells and peripheral lymphoid tissue.


An Online Psychological Program for Adolescents and Young Adults With Headaches: Iterative Design and Rapid Usability Testing.
Headache disorders are common, debilitating health problems. Cognitive-behavioral therapy (CBT) is recommended but rarely easily available. With the use of the internet and communication technologies among youth and young adults, these individuals could be self-trained in CBT skills. There is an increasing number of internet-based interventions for headaches, but there has been little research into the usability of these interventions because evaluating usability across the intervention development life cycle is costly. We developed an internet-based CBT program, the Specialized Program for Headache Reduction (SPHERE). While developing it, we aimed to improve SPHERE through rapid usability testing cycles. This study aims to presents a rapid and affordable usability testing approach that can be performed throughout the intervention development life cycle. This paper also provides evidence of the usability of SPHERE. We used the "think aloud" usability testing method based on Krug's approach to test user interaction within a lab setting. This was followed by a short posttest interview. We planned to test SPHERE with 3-5 participants testing the same part of the program each cycle. Both the design and development team and the research team actively participated in the usability testing process. Observers independently identified the top 3 usability issues, rated their severity, and conducted debriefing sessions to come to consensus on major issues and generate potential solutions. The testing process allowed major usability issues to be identified and rectified rapidly before piloting SPHERE in a real-world context. A total of 2 cycles of testing were conducted. Of the usability issues encountered in cycles 1 and 2, a total of 68% (17/25) and 32% (12/38), respectively, were rated as major, discussed, and fixed. This study shows that rapid usability testing is an essential part of the design process that improves program functionality and can be easy and inexpensive to undertake.


Cross-Jurisdictional Resource Sharing in Changing Public Health Landscape: Contributory Factors and Theoretical Explanations.
Local health departments (LHDs) are striving to meet public health needs within their jurisdictions, amidst fiscal restraints and complex dynamic environment. Resource sharing across jurisdictions is a critical opportunity for LHDs to continue to enhance effectiveness and increase efficiency. This research examines the extent of cross-jurisdictional resource sharing among LHDs, the programmatic areas and organizational functions for which LHDs share resources, and LHD characteristics associated with resource sharing. Data from the National Association of County & City Health Officials' 2013 National Profile of LHDs were used. Descriptive statistics and multinomial logistic regression were performed for the 5 implementation-oriented outcome variables of interest, with 3 levels of implementation. More than 54% of LHDs shared resources such as funding, staff, or equipment with 1 or more other LHDs on a continuous, recurring basis. Results from the multinomial regression analysis indicate that economies of scale (population size and metropolitan status) had significant positive influences (at P ≤ .05) on resource sharing. Engagement in accreditation, community health assessment, community health improvement planning, quality improvement, and use of the Community Guide were associated with lower levels of engagement in resource sharing. Doctoral degree of the top executive and having 1 or more local boards of health carried a positive influence on resource sharing. Cross-jurisdictional resource sharing is a viable and commonly used process to overcome the challenges of new and emerging public health problems within the constraints of restricted budgets. LHDs, particularly smaller LHDs with limited resources, should consider increased resource sharing to address emerging challenges.


Can the use of a rapid polymerase chain screening method decrease the incidence of nosocomial meticillin-resistant Staphylococcus aureus?
Rapid detection of MRSA may be important for the control of MRSA spread in hospitals. The aim of this investigation was to compare the use of a rapid polymerase chain reaction (PCR) screening method with standard culture for the detection of meticillin-resistant Staphylococcus aureus (MRSA) colonisation and to determine its impact on the incidence of MRSA in two hospital wards. During the first phase of the investigation (four months), patients in a surgical ward were screened using the rapid PCR technique and patients in a medical/cardiology ward were screened with standard culture methods. During the second phase of the investigation (four months), MRSA screening methods were switched between the two wards. An audit of infection control practices on each ward was made at the end of each phase in order to check whether any changes had occurred that might influence the risks of MRSA transmission. Use of the rapid PCR method significantly reduced the median time between swabs being taken, to the results being telephoned to the wards (excluding weekends), from 47 to 21 h (P<0.001). However, comparison of MRSA incidence during use of PCR (20/1000 bed-days) and culture methods (22.1/1000 bed-days) revealed no significant difference in incidence on the surgical ward (P=0.69). Regarding the medical/cardiology ward, analysis of data was complicated by an increase in the detection of MRSA during the PCR phase (P<0.05). The study demonstrated that rapid PCR can significantly reduce the turnaround times but reducing the time between swabs being taken to results being telephoned to the ward is still not sufficient to limit the transmission of MRSA.


Primary central nervous system lymphoma: recent progress, many remaining questions.
To review what progress has been made in the treatment of primary central nervous system lymphoma since the time when it was first recognized that high-dose methotrexate based chemotherapy improved outcome over radiation therapy alone. Recent work has explored the use of high-dose methotrexate alone; the optimum dose of methotrexate; the need for intrathecal therapy; combinations of other drugs with high-dose methotrexate, most notably alkylators, high-dose cytarabine, and rituximab; and the use of myeloablative chemotherapy and autologous stem-cell rescue. Recent progress has also been made in the identification of clinical prognostic factors, and in identifying underlying biologic properties that may account for this tumor's distinctive clinical behavior. Further improvement in progression-free survival and in the proportion of patients achieving long-term disease-free survival does seem to be achievable, based on the results of nonrandomized data. Reduction in the risk of severe neurotoxicity by withholding or deferring radiation therapy also appears feasible. Existing treatment options can be individualized to the patient's circumstances. However, the optimal management of primary central nervous system lymphoma remains to be defined, and participation in a suitable clinical trial is highly appropriate.


Testis specific histone 2B is associated with sperm chromatin dynamics and bull fertility-a pilot study.
Bull fertility is the degree of sperm's ability to fertilize and activate the egg and support embryo development, and this is critical for herd reproductive performance. We used the bull as a unique model organism for the study of male fertility because cattle genetics and physiology is similar to those of other mammals including humans. Moreover, reliable fertility data along with well-established in vitro systems are available for bovine. The objective of this original study was to ascertain evolutionary diversification and expression dynamics of Testis Specific Histone 2B (TH2B) in sperm from Holstein bulls with different fertility scores. The intensity of TH2B was determined by using flow cytometry in sperm from 13 high and 13 low fertility bulls. Expression levels of TH2B were measured using immunofluorescence and Western blotting in sperm from five high and five low fertility bulls. Sequence identity, evolutionary distance and interactome of TH2B were evaluated by dotmatcher, STRING and Cytoscape. Data were analyzed using linear mixed effects model and regression plots were drawn. The intensity of TH2B as measured by flow cytometry was significantly affected by an interaction between fertility group and fertility score (P = 0.0182). The intensity of TH2B in sperm from the high fertility group decreased (P = 0.0055) as fertility increased. TH2B was constantly detectable in sperm and expression levels of TH2B decreased in relation to fertility in sperm from the high fertility group (P = 0.018). TH2B biological functions include male gamete generation, chromosome organization, DNA packaging, DNA conformation change, chromatin organization, nucleosome organization, chromatin disassembly, spermatid nucleus elongation, spermatid nucleus differentiation, sperm motility, chromatin organization, chromatin condensation, chromatin silencing, nucleus organization, and chromatin remodeling (P < 0.05). We elucidated the cellular localization and molecular physiology of TH2B using both computational and cell biology approaches. In addition to advancing the fundamental science of mammalian male gamete, the present findings can be potentially used to evaluate semen quality and predict male fertility in the future. This study did not involve any live animals. We did not perform any anesthesia, euthanasia, or any kind of animal sacrifice. The cryopreserved semen samples were obtained from Alta Genetics, Inc., Watertown, WI, USA. All samples were preserved in liquid nitrogen.


ROS-independent Nrf2 activation in prostate cancer.
In prostate cancer, oxidative stress and the subsequent Nrf2 activation promote the survival of cancer cells and acquired chemoresistance. Nrf2 links prostate cancer to endoplasmic reticulum stress, an event that triggers the unfolded protein response, aiming to restore cellular homeostasis as well as an adaptive survival mechanism. Glucose-regulated protein of 78 kD /immunoglobulin heavy chain binding protein (GRP78/BiP) is a key molecular chaperone in the endoplasmic reticulum that, when expressed at the cell surface, acts as a receptor for several signaling pathways enhancing antiapoptotic and proliferative signals. We showed GRP78/BiP translocation to PC3 cell surface in the presence of tunicamycin, an ER stress inductor, and demonstrated the existence of a GRP78/BiP-dependent non-canonical Nrf2 activation, responsible for increased resistance to ER-stress induced apoptosis. We found that, even in the absence of ROS production, tunicamycin causes Nrf2 activation, and activates Akt signaling, events bulnted by anti-GRP78/BiP antibody treatment. The presence of GRP78/BiP at the cell surface might be exploited for the immunotherapeutic strategy of prostate cancer since its blockage by anti-GRP78/BiP antibodies might promote cancer death by suppressing some of the several molecular protective mechanisms found in aggressive cancer cells.


Selective Attention to Faces in a Rapid Visual Stream: Hemispheric Differences in Enhancement and Suppression of Category-selective Neural Activity.
In daily life, efficient perceptual categorization of faces occurs in dynamic and highly complex visual environments. Yet the role of selective attention in guiding face categorization has predominantly been studied under sparse and static viewing conditions, with little focus on disentangling the impact of attentional enhancement and suppression. Here we show that attentional enhancement and suppression exert a differential impact on face categorization supported by the left and right hemispheres. We recorded 128-channel EEG while participants viewed a 6-Hz stream of object images (buildings, animals, objects, etc.) with a face image embedded as every fifth image (i.e., OOOOFOOOOFOOOOF…). We isolated face-selective activity by measuring the response at the face presentation frequency (i.e., 6 Hz/5 = 1.2 Hz) under three conditions: Attend Faces, in which participants monitored the sequence for instances of female faces; Attend Objects, in which they responded to instances of guitars; and Baseline, in which they performed an orthogonal task on the central fixation cross. During the orthogonal task, face-specific activity was predominantly centered over the right occipitotemporal region. Actively attending to faces enhanced face-selective activity much more evidently in the left hemisphere than in the right, whereas attending to objects suppressed the face-selective response in both hemispheres to a comparable extent. In addition, the time courses of attentional enhancement and suppression did not overlap. These results suggest the left and right hemispheres support face-selective processing in distinct ways-where the right hemisphere is mandatorily engaged by faces and the left hemisphere is more flexibly recruited to serve current tasks demands.


Determining Potentials of Zero Charge of Metal Electrodes versus the Standard Hydrogen Electrode from Density-Functional-Theory-Based Molecular Dynamics.
We develop a computationally efficient scheme to determine the potentials of zero charge (PZC) of metal-water interfaces with respect to the standard hydrogen electrode. We calculate the PZC of Pt(111), Au(111), Pd(111) and Ag(111) at a good accuracy using this scheme. Moreover, we find that the interface dipole potentials are almost entirely caused by charge transfer from water to the surfaces, the magnitude of which depends on the bonding strength between water and the metals, while water orientation hardly contributes at the PZC conditions.


The multifunctional role of intrinsic disorder in NF-κB signaling.
The nuclear factor-κB (NF-κB) transcription activation system involves disordered regions of both the NF-κB dimers and their inhibitors, the IκBs. The system is well-studied both at the cellular and biophysical levels affording a unique opportunity to compare and contrast the conclusions from both types of experiments. Through a combination of both experiments and theory, we have discovered that the RelA/p50 heterodimer and its inhibitor IκBα operate under kinetic control. Intrinsically disordered parts of both proteins are directly involved in temporal control and their folding and unfolding determines the rates of various processes. In this review, we show how the dynamic state of the intrinsically disordered sequences define the rates of intracellular processes.


The LPL gene in individuals with familial combined hyperlipidemia and decreased LPL activity.
Familial combined hyperlipidemia (FCHL) is an oligogenic disorder, with family members having elevated apolipoprotein B-100 levels and either elevated plasma cholesterol or triglyceride levels or both. Obligate heterozygous parents of children with lipoprotein lipase (LPL) deficiency express a mild FCHL phenotype. Of patients with FCHL, 36% have diminished postheparin LPL activity and mass values that are comparable with those of obligate heterozygotes for LPL deficiency. It is hypothesized that heterozygosity for mutations in the LPL gene could contribute to FCHL in this subset of patients. Single-strand conformation polymorphism (SSCP) analysis, direct DNA sequencing, and Southern blot analysis were used to examine exons 1 through 9 and exon-intron junctions of the LPL gene in 20 patients with FCHL and low LPL activity and mass. One subject had a substitution (GAC-->AAC) in exon 2, changing Asp9 to Asn. Two subjects had a previously undescribed "silent" substitution (GTG-->GTA) in exon 3 at Val108. Three patients had a premature termination at codon 447 in exon 9 resulting in truncation of the mature protein by two amino acids. In addition to SSCP analysis, exons 4, 5, and 6, where almost all mutations in LPL-deficient patients have been found, were sequenced and no additional mutations were found. Southern blot analysis of the LPL gene revealed one subject with heterozygous loss of an EcoRI site but without an abnormality in Stu I restriction fragments; this mutation is therefore unlikely to be functionally significant. The substitutions identified at codons 9 and 447 have previously been found not to affect lipolytic activity when expressed in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)


Pathogenesis of bat rabies in a natural reservoir: Comparative susceptibility of the straw-colored fruit bat (Eidolon helvum) to three strains of Lagos bat virus.
Rabies is a fatal neurologic disease caused by lyssavirus infection. People are infected through contact with infected animals. The relative increase of human rabies acquired from bats calls for a better understanding of lyssavirus infections in their natural hosts. So far, there is no experimental model that mimics natural lyssavirus infection in the reservoir bat species. Lagos bat virus is a lyssavirus that is endemic in straw-colored fruit bats (Eidolon helvum) in Africa. Here we compared the susceptibility of these bats to three strains of Lagos bat virus (from Senegal, Nigeria, and Ghana) by intracranial inoculation. To allow comparison between strains, we ensured the same titer of virus was inoculated in the same location of the brain of each bat. All bats (n = 3 per strain) were infected, and developed neurological signs, and fatal meningoencephalitis with lyssavirus antigen expression in neurons. There were three main differences among the groups. First, time to death was substantially shorter in the Senegal and Ghana groups (4 to 6 days) than in the Nigeria group (8 days). Second, each virus strain produced a distinct clinical syndrome. Third, the spread of virus to peripheral tissues, tested by hemi-nested reverse transcriptase PCR, was frequent (3 of 3 bats) and widespread (8 to 10 tissues positive of 11 tissues examined) in the Ghana group, was frequent and less widespread in the Senegal group (3/3 bats, 3 to 6 tissues positive), and was rare and restricted in the Nigeria group (1/3 bats, 2 tissues positive). Centrifugal spread of virus from brain to tissue of excretion in the oral cavity is required to enable lyssavirus transmission. Therefore, the Senegal and Ghana strains seem most suitable for further pathogenesis, and for transmission, studies in the straw-colored fruit bat.


Thalassemias: simple screening for hereditary anemias.
The most prevalent hemoglobinopathies in the world, thalassemias are hereditary microcytic anemias. Each year, 100,000 children throughout the world are born with thalassemia major, a fatal blood disease. Thalassemia minor is the carrier state for this catastrophic disease. Health practitioners can easily identify patients who may have thalassemia minor through evaluation of routine red-blood-cell indices, and diagnosis can be confirmed by Hgb A2 evaluation. Once individuals know they have thalassemia minor, a lifetime of unnecessary treatment for anemia can be avoided. Patient education should also include information about preconception counseling and partner screening. Recognition of the potential for congenital diseases and subsequent screening or referral are the responsibilities of all health care practitioners who see clients before and during their reproductive years.


Thermal transport across nanoparticle-fluid interfaces: the interplay of interfacial curvature and nanoparticle-fluid interactions.
We investigate the general dependence of the thermal transport across nanoparticle-fluid interfaces using molecular dynamics computations. We show that the thermal conductance depends strongly both on the wetting characteristics of the nanoparticle-fluid interface and on the nanoparticle size. Strong nanoparticle-fluid interactions, leading to full wetting states in the host fluid, result in high thermal conductances and efficient interfacial transport of heat. Weak interactions result in partial drying or full drying states, and low thermal conductances. The variation of the thermal conductance with particle size is found to depend on the fluid-nanoparticle interactions. Strong interactions coupled with large interfacial curvatures lead to optimum interfacial heat transport. This complex dependence can be modelled using an equation that includes the interfacial curvature as a parameter. In this way, we rationalise the existing experimental and computer simulation results and show that the thermal transport across nanoscale interfaces is determined by the correlations of both interfacial curvature and nanoparticle-fluid interactions.


MRI usage in a pediatric emergency department: an analysis of usage and usage trends over 5 years.
Magnetic resonance imaging (MRI) usage has anecdotally increased due to the principles of ALARA and the desire to Image Gently. Aside from a single abstract in the emergency medicine literature, pediatric emergency department MRI usage has not been described. Our objective was to determine whether MRI use is indeed increasing at a high-volume urban pediatric emergency department with 24/7 MRI availability. Also, we sought to determine which exams, time periods and demographics influenced the trend. Institutional Review Board exemption was obtained. Emergency department patient visit and exam data were obtained from the hospital database for the 2011-2015 time period. MRI usage data were normalized using emergency department patient visit data to determine usage rates. The z-test was used to compare MRI use by gender. The chi-square test was used to test for trends in MRI usage during the study period and in patient age. MRI usage for each hour and each weekday were tabulated to determine peak and trough usage times. MRI usage rate per emergency department patient visit was 0.36%. Headache, pain and rule-out appendicitis were the most common indications for neuroradiology, musculoskeletal and trunk exams, respectively. Usage in female patients was significantly greater than in males (0.42% vs. 0.29%, respectively, P<0.001). Usage significantly increased during the 5-year period (P<0.001). Use significantly increased from age 3 to 17 (0.011% to 1.1%, respectively, P<0.001). Sixty percent of exams were performed after-hours, the highest volume during the 10 p.m. hour and lowest between 4 a.m. and 9 a.m. MRI use was highest on Thursdays and lowest on Sundays (MRI on 0.45% and 0.22% of patients, respectively). MRI use in children increased during the study period, most notably in females, on weekdays and after-hours.


Azole-containing cationic bis-cyclometallated iridium(iii) isocyanide complexes: a theoretical insight into the emission energy and emission efficiency.
Using a density functional theory approach, we explore the emission properties of a family of bis-cyclometallated cationic iridium(iii) complexes of general formula [Ir(C^N)2(CN-tert-Bu)2]+ that have tert-butyl isocyanides as neutral auxiliary ligands. Taking the [Ir(ppy)2(CN-tert-Bu)2]+ complex (Hppy = 2-phenylpyridine) as a reference, the effect of replacing the pyridine ring in the cyclometallating ppy ligand by a five-membered azole ring has been examined. To this end, two series of complexes differing by the nature of the atom (either nitrogen or carbon) linking the azole to the phenyl ring of the cyclometallating ligand have been designed. Each series is composed of three molecules having an increasing number of nitrogen atoms (2 to 4) in the azole ring. The emission energies computed for the azole-containing [Ir(C^N)2(CN-tert-Bu)2]+ complexes show a generalized blue-shift compared to [Ir(ppy)2(CN-tert-Bu)2]+, in agreement with the experimental data available for two of the six complexes designed here. The electronic nature of the lowest-lying triplet (T1) is clearly established as a ligand-centred (3LC) state associated with the cyclometallating ligands, and cannot be described as a simple HOMO → LUMO promotion. Therefore, no clear trend based on the sole use of molecular orbital energies can be inferred to predict the emission properties. The significant oscillation in the emission quantum yield (ranging from 0.1% to 52%) experimentally reported is rationalized by the energy gap between the emitting T1 state and a non-radiative triplet state having metal-centred (3MC) d-d* nature. On the basis of such a model, two of the here proposed systems are expected to display significant emission quantum yields in the blue region of the visible spectra, which make them good candidates for electroluminescent applications.


Video decision support tool for advance care planning in dementia: randomised controlled trial.
To evaluate the effect of a video decision support tool on the preferences for future medical care in older people if they develop advanced dementia, and the stability of those preferences after six weeks. Randomised controlled trial conducted between 1 September 2007 and 30 May 2008. Setting Four primary care clinics (two geriatric and two adult medicine) affiliated with three academic medical centres in Boston. Convenience sample of 200 older people (>or=65 years) living in the community with previously scheduled appointments at one of the clinics. Mean age was 75 and 58% were women. Verbal narrative alone (n=106) or with a video decision support tool (n=94). Preferred goal of care: life prolonging care (cardiopulmonary resuscitation, mechanical ventilation), limited care (admission to hospital, antibiotics, but not cardiopulmonary resuscitation), or comfort care (treatment only to relieve symptoms). Preferences after six weeks. The principal category for analysis was the difference in proportions of participants in each group who preferred comfort care. Among participants receiving the verbal narrative alone, 68 (64%) chose comfort care, 20 (19%) chose limited care, 15 (14%) chose life prolonging care, and three (3%) were uncertain. In the video group, 81 (86%) chose comfort care, eight (9%) chose limited care, four (4%) chose life prolonging care, and one (1%) was uncertain (chi(2)=13.0, df=3, P=0.003). Among all participants the factors associated with a greater likelihood of opting for comfort care were being a college graduate or higher, good or better health status, greater health literacy, white race, and randomisation to the video arm. In multivariable analysis, participants in the video group were more likely to prefer comfort care than those in the verbal group (adjusted odds ratio 3.9, 95% confidence interval 1.8 to 8.6). Participants were re-interviewed after six weeks. Among the 94/106 (89%) participants re-interviewed in the verbal group, 27 (29%) changed their preferences (kappa=0.35). Among the 84/94 (89%) participants re-interviewed in the video group, five (6%) changed their preferences (kappa=0.79) (P<0.001 for difference). Older people who view a video depiction of a patient with advanced dementia after hearing a verbal description of the condition are more likely to opt for comfort as their goal of care compared with those who solely listen to a verbal description. They also have more stable preferences over time. Clinicaltrials.gov NCT00704886.


Control of dorsoventral pattern in the chick paraxial mesoderm.
The most profound feature of the mature vertebrate somite is its organisation into dorsal dermomyotome, intermediate myotome and ventral sclerotome. We analysed the role of potential signalling structures in this dorsoventral pattern by ablating them or transplanting them to ectopic locations in chick embryos. Our data suggest that the somite represents a naive tissue, entirely depending on external cues for its dorsoventral organisation. Dorsalisation by signals from dorsal neural tube and surface ectoderm stimulates the development of the dermomyotome. Likewise, signals from notochord and floor plate ventralise the somite, at high levels overriding any dorsal information and inducing the sclerotome. The dorsalising factors and lower levels of the ventralising factors act in concert to induce the myotome. Finally, the paraxial mesoderm intrinsically controls its competence to respond to the external inducers.


More than a simple biomarker: the role of NGAL in cardiovascular and renal diseases.
Neutrophil gelatinase-associated lipocalin (NGAL) is a small circulating protein that is highly modulated in a wide variety of pathological situations, making it a useful biomarker of various disease states. It is one of the best markers of acute kidney injury, as it is rapidly released after tubular damage. However, a growing body of evidence highlights an important role for NGAL beyond that of a biomarker of renal dysfunction. Indeed, numerous studies have demonstrated a role for NGAL in both cardiovascular and renal diseases. In the present review, we summarize current knowledge concerning the involvement of NGAL in cardiovascular and renal diseases and discuss the various mechanisms underlying its pathological implications.


Toward the development of national telehealth services: the role of Veterans Health Administration and future directions for research.
The Veterans Health Administration (VHA) in the Department of Veteran Affairs (VA) has emerged as a national and international leader in the delivery and research of telehealth-based treatment. Several unique characteristics of care in VA settings intersect to create an ideal environment for telehealth modalities and research. However, the value of telehealth experience and initiatives in VA settings is limited if telehealth strategies cannot be widely exported to other public or private systems. Whereas a hierarchical organization, such as VA, can innovate and fund change relatively quickly based on provider and patient preferences and a growing knowledge base, other health provider organizations and third-party payers may likely require replicable scientific findings over time before incremental investments will be made to create infrastructure, reform regulatory barriers, and amend laws to accommodate expansion of telehealth modalities. Accordingly, large-scale scientifically rigorous telehealth research in VHA settings is essential not only to investigate the efficacy of existing and future telehealth practices in VHA, but also to hasten the development of telehealth infrastructure in private and other public health settings. We propose an expanded partnership between the VA, NIH, and other funding agencies to investigate creative and pragmatic uses of telehealth technology. To this end, we identify six specific areas of research we believe to be particularly relevant to the efficient development of telehealth modalities in civilian and military contexts outside VHA.


T1 mapping of the myocardium: intra-individual assessment of post-contrast T1 time evolution and extracellular volume fraction at 3T for Gd-DTPA and Gd-BOPTA.
Myocardial T1 relaxation time (T1 time) and extracellular volume fraction (ECV) are altered in patients with diffuse myocardial fibrosis. The purpose of this study was to perform an intra-individual assessment of normal T1 time and ECV for two different contrast agents. A modified Look-Locker Inversion Recovery (MOLLI) sequence was acquired at 3 T in 24 healthy subjects (8 men; 28 ± 6 years) at mid-ventricular short axis pre-contrast and every 5 min between 5-45 min after injection of a bolus of 0.15 mmol/kg gadopentetate dimeglumine (Gd-DTPA; Magnevist®) (exam 1) and 0.1 mmol/kg gadobenate dimeglumine (Gd-BOPTA; Multihance®) (exam 2) during two separate scanning sessions. T1 times were measured in myocardium and blood on generated T1 maps. ECVs were calculated as ΔR1 myocardium/ΔR1 blood*1-hematocrit. Mean pre-contrast T1 relaxation times for myocardium and blood were similar for both the first and second CMR exam (p > 0.5). Overall mean post-contrast myocardial T1 time was 15 ± 2 ms (2.5 ± 0.7%) shorter for Gd-DTPA at 0.15 mmol/kg compared to Gd-BOPTA at 0.1 mmol/kg (p < 0.01) while there was no significant difference for T1 time of blood pool (p > 0.05). Between 5 and 45 minutes after contrast injection, mean ECV values increased linearly with time for both contrast agents from 0.27 ± 0.03 to 0.30 ± 0.03 (p < 0.0001). Mean ECV values were slightly higher (by 0.01, p < 0.05) for Gd-DTPA compared to Gd-BOPTA. Inter-individual variation of ECV was higher (CV 8.7% [exam 1, Gd-DTPA] and 9.4% [exam 2, Gd-BOPTA], respectively) compared to variation of pre-contrast myocardial T1 relaxation time (CV 4.5% [exam 1] and 3.0% [exam 2], respectively). ECV with Gd-DTPA was highly correlated to ECV by Gd-BOPTA (r = 0.803; p < 0.0001). In comparison to pre-contrast myocardial T1 relaxation time, variation in ECV values of normal subjects is larger. However, absolute differences in ECV between Gd-DTPA and Gd-BOPTA were small and rank correlation was high. There is a small and linear increase in ECV over time, therefore ideally images should be acquired at the same delay after contrast injection.


Optimization of Method for Human Sex Determination Using Peptidome Analysis of Teeth Enamel from Teeth of Different Biological Generation, Archeological Age, and Degrees of Taphonomic Preservation.
Determination of biological sex to human remains is a fundamental requirement in anthropological, archeological, and forensic anthropological studies. Sex determination based on morphological criteria is significantly limited in the cases of juvenile remains and adult skeletons in a poor state of preservation. Regular attempts have been made to use alternative techniques to resolve this issue, including analysis of tooth enamel peptides by liquid chromatography/mass spectrometry. Optimization of this method involving acid etching of tooth enamel for 10 min followed by desalting of the products of etching on SDB-RPS StageTips microcolumns and analysis of desalted sample (1/3) by liquid chromatography/mass spectrometry allowed reliable sex determination to fossil remains within a wide range of archeological and biological ages without destructing analyzed teeth. Increasing the duration of enamel etching ensured a 2 to 3-fold increase in the total number of identified peptides and, more importantly, in the number of identified fragments of amelogenin Y isoform specific for male teeth, which facilitated reliable sex determination of fossil remains. The suggested technique was tested with 8 permanent and 15 deciduous teeth of different archaeological age and different degree of preservation. Two amelogenin Y-specific peptide sequences were identified. One of these peptides [SM(+15.99)IRPPYS)] was found in all male-derived samples without exception; the other peptide [IRPPYSS(+79.97)], which contained phosphorylated Ser66 residue, was found only in the enamel from deciduous teeth, which suggests that phosphorylation of Ser66 plays a role in the enamel formation in deciduous teeth.


IgE-Mediated Peanut Allergy: Current and Novel Predictive Biomarkers for Clinical Phenotypes Using Multi-Omics Approaches.
Food allergy is a collective term for several immune-mediated responses to food. IgE-mediated food allergy is the best-known subtype. The patients present with a marked diversity of clinical profiles including symptomatic manifestations, threshold reactivity and reaction kinetics. In-vitro predictors of these clinical phenotypes are evasive and considered as knowledge gaps in food allergy diagnosis and risk management. Peanut allergy is a relevant disease model where pioneer discoveries were made in diagnosis, immunotherapy and prevention. This review provides an overview on the immune basis for phenotype variations in peanut-allergic individuals, in the light of future patient stratification along emerging omic-areas. Beyond specific IgE-signatures and basophil reactivity profiles with established correlation to clinical outcome, allergenomics, mass spectrometric resolution of peripheral allergen tracing, might be a fundamental approach to understand disease pathophysiology underlying biomarker discovery. Deep immune phenotyping is thought to reveal differential cell responses but also, gene expression and gene methylation profiles (eg, peanut severity genes) are promising areas for biomarker research. Finally, the study of microbiome-host interactions with a focus on the immune system modulation might hold the key to understand tissue-specific responses and symptoms. The immune mechanism underlying acute food-allergic events remains elusive until today. Deciphering this immunological response shall enable to identify novel biomarker for stratification of patients into reaction endotypes. The availability of powerful multi-omics technologies, together with integrated data analysis, network-based approaches and unbiased machine learning holds out the prospect of providing clinically useful biomarkers or biomarker signatures being predictive for reaction phenotypes.


Selective targeting of death receptor 5 circumvents resistance of MG-63 osteosarcoma cells to TRAIL-induced apoptosis.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a tumor necrosis factor superfamily member, targets death receptors and selectively kills malignant cells while leaving normal cells unaffected. However, unlike most cancers, many osteosarcomas are resistant to TRAIL. To investigate this resistance, we characterized the response of MG-63 osteosarcoma cells and hPOB-tert osteoblast-like cells to TRAIL and agonist antibodies to death receptor 4 (DR4) and death receptor 5 (DR5). We found that MG-63 osteosarcoma cells and hPOB-tert osteoblast-like cells show no or very little response to TRAIL or a DR4 agonist, but MG-63 cells undergo apoptosis in response to a DR5 agonist. Analysis of TRAIL receptor expression showed that normal osteoblastic and osteosarcoma cells express a variety of TRAIL receptors but this does not correlate to TRAIL responsiveness. Production of the soluble decoy receptor osteoprotegerin also could not explain TRAIL resistance. We show that TRAIL activates the canonical caspase-dependent pathway, whereas treatment with cycloheximide increases the sensitivity of MG-63 cells to TRAIL and anti-DR5 and can also sensitize hPOB-tert cells to both agents. Proapoptotic and antiapoptotic protein expression does not significantly differ between MG-63 and hPOB-tert cells or change following treatment with TRAIL or anti-DR5. However, sequencing the death domain of DR4 in several osteoblast-like cells showed that MG-63 osteosarcoma cells are heterozygous for a dominant-negative mutation, which can confer TRAIL resistance. These results suggest that although the dominant-negative form of the receptor may block TRAIL-induced death, an agonist antibody to the active death receptor can override cellular defenses and thus provide a tailored approach to treat resistant osteosarcomas.


Individualizing Care for Patients With Myeloproliferative Neoplasms: Integrating Genetics, Evolving Therapies, and Patient-Specific Disease Burden.
Individualized medicine is important for patients with myeloproliferative neoplasms (MPNs), including essential thrombocythemia, polycythemia vera, and myelofibrosis, which are heterogeneous in terms of genetic mutation profile, prognosis, disease burden, and symptoms. Status of MPN driver mutations in JAK2, CALR, and MPL (or lack of one of these mutations) and other myeloid mutations (ASXL1, SRSF2, CBL, and IDH1/2, among others) affects diagnosis and prognosis. Management begins with estimating the prognosis, disease burden including MPN symptoms, and prevention of vascular events. Allogeneic stem cell transplantation is the definitive therapy in a subset of patients with myelofibrosis, the majority of whom receive JAK inhibition with ruxolitinib to relieve splenomegaly and symptoms and to prolong survival. Ruxolitinib is now a second-line therapy in polycythemia vera, with pegylated interferon being evaluated as a potential front-line therapy compared with hydroxyurea. The therapeutic landscape is evolving to include new JAK inhibitors, which may affect cytopenias (pacritinib and momelotinib), combination therapies including ruxolitinib, and novel targets such as pentraxin and telomerase. Assessing the therapeutic efficacy (including symptom impact) and toxicity of these new approaches is necessary to determine longitudinal management of MPNs in clinical practice and is a key component of "individualizing" care for patients with MPNs.


Insulin cessation and diabetes remission after bariatric surgery in adults with insulin-treated type 2 diabetes.
The impact of bariatric surgeries on insulin-treated type 2 diabetes (I-T2D) in the general population is largely undocumented. We assessed changes in insulin treatment after bariatric surgery in a large cohort of I-T2D patients, comparing Roux-en-Y gastric bypass surgery (RYGB) with laparoscopic adjustable gastric banding (LAGB), controlling for differences in weight loss between procedures. Of 113,638 adult surgical patients in the Bariatric Outcomes Longitudinal Database (BOLD), 10% had I-T2D. Analysis was restricted to 5,225 patients with I-T2D and at least 1 year of postoperative follow-up. Regression models were used to identify factors that predict cessation of insulin therapy. To control for differences in weight loss patterns between RYGB and LAGB, a case-matched analysis was also performed. Of I-T2D patients who underwent RYGB (n = 3,318), 62% were off insulin at 12 months compared with 34% (n = 1,907) after LAGB (P < 0.001). Regression analysis indicated that RYGB strongly predicted insulin cessation at both 1 and 12 months postoperatively. In the case-matched analysis at 3 months, the proportion of insulin cessation was significantly higher in the RYGB group than in the LAGB group (P = 0.03), and the diabetes remission rate was higher at all time points after this surgery. RYGB was a weight-independent predictor of insulin therapy cessation early after surgery, whereas insulin cessation after LAGB was linked to weight loss. I-T2D patients have a greater probability of stopping insulin after RYGB than after LAGB (62% vs. 34%, respectively, at 1 year), with weight-independent effects in the early months after surgery. These findings support RYGB as the procedure of choice for reversing I-T2D.


Immune response to HIV-1 gag antigens induced by recombinant adenovirus vectors in mice and rhesus macaque monkeys.
Recombinant adenovirus vectors expressing the entire gag (p55) or CA (p24) region of human immunodeficiency virus type 1 (HIV-1) were constructed by inserting the appropriate HIV DNA sequences into the E3 region of human adenovirus type 5 (Ad5) with and without an exogenous SV40 early promoter. The infectious recombinant adenoviruses Adgag1, AdSVgag1, and AdSVCA1 were shown to express the appropriate HIV-1 antigens in human cells in vitro, as measured by immunoprecipitation and p24 antigen capture assays. Using the p24 antigen capture assay, HIV antigen expressed by AdSVCA1 was detected earlier in infection and in greater amounts than that produced by either Adgag1 or AdSVgag1. In studies concerning the immunogenicity of these vectors, Balb/c (H-2d) mice given a single intraperitoneal injection of 10(7) or 10(8) plaque-forming units of purified vector developed serum antibodies to p24, detected by Western blotting, by 2 weeks postinjection. In the preliminary test of the immunogenicity of the recombinant adenovirus vectors in primates, two of four rhesus macaque monkeys generated antibodies to HIV-1 p24 following two injections of AdSVCA1. As expected, monkeys injected with control adenovirus failed to show any anti-HIV response, and none of the monkeys showed any adverse reactions following infection with either recombinant or control adenoviruses. These results suggest that adenovirus vectors have considerable potential in the study of possible immune therapies for HIV infection.


Pint lincRNA connects the p53 pathway with epigenetic silencing by the Polycomb repressive complex 2.
The p53 transcription factor is located at the core of a complex wiring of signaling pathways that are critical for the preservation of cellular homeostasis. Only recently it has become clear that p53 regulates the expression of several long intergenic noncoding RNAs (lincRNAs). However, relatively little is known about the role that lincRNAs play in this pathway. Here we characterize a lincRNA named Pint (p53 induced noncoding transcript). We show that Pint is aubiquitously expressed lincRNA that is finely regulated by p53. In mouse cells, Pint promotes cell proliferation and survival by regulating the expression of genes of the TGF-b, MAPK and p53 pathways. Pint is a nuclear lincRNA that directly interacts with the Polycomb repressive complex 2 (PRC2), and is required for PRC2 targeting of specific genes for H3K27 tri-methylation and repression. Furthermore, Pint functional activity is highly dependent on PRC2 expression. We have also identified Pint human ortholog (PINT), which presents suggestive analogies with the murine lincRNA. PINT is similarly regulated by p53, and its expression significantly correlates with the same cellular pathways as the mouse ortholog, including the p53 pathway. Interestingly, PINT is downregulated in colon primary tumors, while its overexpression inhibits the proliferation of tumor cells, suggesting a possible role as tumor suppressor. Our results reveal a p53 autoregulatory negative mechanism where a lincRNA connects p53 activation with epigenetic silencing by PRC2. Additionally, we show analogies and differences between the murine and human orthologs, identifying a novel tumor suppressor candidate lincRNA.


OpenKnowledge for peer-to-peer experimentation in protein identification by MS/MS.
Traditional scientific workflow platforms usually run individual experiments with little evaluation and analysis of performance as required by automated experimentation in which scientists are being allowed to access numerous applicable workflows rather than being committed to a single one. Experimental protocols and data under a peer-to-peer environment could potentially be shared freely without any single point of authority to dictate how experiments should be run. In such environment it is necessary to have mechanisms by which each individual scientist (peer) can assess, locally, how he or she wants to be involved with others in experiments. This study aims to implement and demonstrate simple peer ranking under the OpenKnowledge peer-to-peer infrastructure by both simulated and real-world bioinformatics experiments involving multi-agent interactions. A simulated experiment environment with a peer ranking capability was specified by the Lightweight Coordination Calculus (LCC) and automatically executed under the OpenKnowledge infrastructure. The peers such as MS/MS protein identification services (including web-enabled and independent programs) were made accessible as OpenKnowledge Components (OKCs) for automated execution as peers in the experiments. The performance of the peers in these automated experiments was monitored and evaluated by simple peer ranking algorithms. Peer ranking experiments with simulated peers exhibited characteristic behaviours, e.g., power law effect (a few dominant peers dominate), similar to that observed in the traditional Web. Real-world experiments were run using an interaction model in LCC involving two different types of MS/MS protein identification peers, viz., peptide fragment fingerprinting (PFF) and de novo sequencing with another peer ranking algorithm simply based on counting the successful and failed runs. This study demonstrated a novel integration and useful evaluation of specific proteomic peers and found MASCOT to be a dominant peer as judged by peer ranking. The simulated and real-world experiments in the present study demonstrated that the OpenKnowledge infrastructure with peer ranking capability can serve as an evaluative environment for automated experimentation.


ABPP-HT - High-Throughput Activity-Based Profiling of Deubiquitylating Enzyme Inhibitors in a Cellular Context.
The potency and selectivity of a small molecule inhibitor are key parameters to assess during the early stages of drug discovery. In particular, it is very informative for characterizing compounds in a relevant cellular context in order to reveal potential off-target effects and drug efficacy. Activity-based probes are valuable tools for that purpose, however, obtaining cellular target engagement data in a high-throughput format has been particularly challenging. Here, we describe a new methodology named ABPP-HT (high-throughput-compatible activity-based protein profiling), implementing a semi-automated proteomic sample preparation workflow that increases the throughput capabilities of the classical ABPP workflow approximately ten times while preserving its enzyme profiling characteristics. Using a panel of deubiquitylating enzyme (DUB) inhibitors, we demonstrate the feasibility of ABPP-HT to provide compound selectivity profiles of endogenous DUBs in a cellular context at a fraction of time as compared to previous methodologies.


Perceived value of eHealth among people living with multimorbidity: a qualitative study.
The prevalence of multimorbidity is increasing, creating challenges for patients, healthcare professionals, and healthcare systems. Given that chronic disease management increasingly involves eHealth, it is useful to assess its perceived value among people with multimorbidity. To explore challenges related to multimorbidity and patients' perspectives on eHealth. Ten semi-structured interviews with adults, living with multimorbidity in Copenhagen, Denmark. Interviews focused on patient-experienced challenges, from challenges related to self-management to challenges experienced in the healthcare sector, as well as perceptions of eHealth. During interviews, participants were presented with pictures of different eHealth technologies. Data analysis followed the systematic text condensation approach. Participants experienced challenges in their daily lives, e.g. when practicing self-management activities, when navigating the healthcare sector, and when interacting with healthcare professionals. Patient-perceived value of eHealth varied, depending on their burden of illness and treatment: those with a greater burden had more positive perceptions of eHealth, and expressed more intention to use it. Participants with less complex disease patterns and less burdensome treatment regimens were more likely to perceive eHealth as something worthless and undesirable. Participants stressed that eHealth should only be introduced as an optional supplement. eHealth can potentially address some patient-experienced challenges related to multimorbidity by promoting self-management, patient-centeredness, and access. However, patients' needs and preferences vary and eHealth cannot substitute the personal interaction between patient and healthcare professionals. Our findings point to the importance of patient assessment and stratification to ensure appropriate use of eHealth.


The Effect of Lean-Seafood and Non-Seafood Diets on Fasting and Postprandial Serum Metabolites and Lipid Species: Results from a Randomized Crossover Intervention Study in Healthy Adults.
The metabolic effects associated with intake of different dietary protein sources are not well characterized. We aimed to elucidate how two diets that varied in main protein sources affected the fasting and postprandial serum metabolites and lipid species. In a randomized controlled trial with crossover design, healthy adults (n = 20) underwent a 4-week intervention with two balanced diets that varied mainly in protein source (lean-seafood versus non-seafood proteins). Nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry analyses were applied to examine the effects of the two diets on serum metabolites. In the fasting state, the lean-seafood diet period, as opposed to the non-seafood diet period, significantly decreased the serum levels of isoleucine and valine, and during the postprandial state, a decreased level of lactate and increased levels of citrate and trimethylamine N-oxide were observed. The non-seafood diet significantly increased the fasting level of 26 lipid species including ceramides 18:1/14:0 and 18:1/23:0 and lysophosphatidylcholines 20:4 and 22:5, as compared to the lean-seafood diet. Thus, the lean-seafood diet decreased circulating isoleucine and valine levels, whereas the non-seafood diet elevated the levels of certain ceramides, metabolites that are associated with insulin-resistance.


Examining the visual processing patterns of lonely adults.
Prior research has shown that loneliness is associated with hypervigilance to social threats, with eye-tracking research showing lonely people display a specific attentional bias when viewing social rejection and social exclusion video footage (Bangee, Harris, Bridges, Rotenberg & Qualter, 2014; Qualter, Rotenberg, Barrett et al., 2013). The current study uses eye-tracker methodology to examine whether that attentional bias extends to negative emotional faces and negative social non-rejecting stimuli, or whether it could be explained only as a specific bias to social rejection/exclusion. It is important to establish whether loneliness relates to a specific or general attention bias because it may explain the maintenance of loneliness. Participants (N = 43, F = 35, Mage = 20 years and 2 months, SD = 3 months) took part in three tasks, where they viewed different social information: Task 1 - slides displaying four faces each with different emotions (anger, afraid, happy and neutral), Task 2 - slides displaying sixteen faces with varying ratios expressing happiness and anger, and Task 3 - slides displaying four visual scenes (socially rejecting, physically threatening, socially positive, neutral). For all three tasks, eye movements were recorded in real time with an eye-tracker. Results showed no association between loneliness and viewing patterns of facial expressions, but an association between loneliness and hypervigilant viewing of social rejecting stimuli. The findings indicate that lonely adults do not have a generalised hypervigilance to social threat, but have, instead, a specific attentional bias to rejection information in social contexts. Implications of the findings for interventions are discussed.