Characterisation of urinary WFDC12 in small nocturnal basal primates, mouse lemurs (Microcebus spp.)

Mouse lemurs are basal primates that rely on chemo- and acoustic signalling for social interactions in their dispersed social systems. We examined the urinary protein content of two mouse lemurs species, within and outside the breeding season, to assess candidates used in species discrimination, reproductive or competitive communication. Urine from Microcebus murinus and Microcebus lehilahytsara contain a predominant 10 kDa protein, expressed in both species by some, but not all, males during the breeding season, but at very low levels by females. Mass spectrometry of the intact proteins confirmed the protein mass and revealed a 30 Da mass difference between proteins from the two species. Tandem mass spectrometry after digestion with three proteases and sequencing de novo defined the complete protein sequence and located an Ala/Thr difference between the two species that explained the 30 Da mass difference. The protein (mature form: 87 amino acids) is an atypical member of the whey acidic protein family (WFDC12). Seasonal excretion of this protein, species difference and male-specific expression during the breeding season suggest that it may have a function in intra- and/or intersexual chemical signalling in the context of reproduction, and could be a cue for sexual selection and species recognition

Factors affecting the intention of providers to deliver more effective continuing medical education to general practitioners: a pilot study

BACKGROUND: Despite the importance of continuing medical education (CME) for GPs, there has been little research into how providers decide what types of CME to deliver to GPs. This study aimed to identify factors affecting the intention of providers to provide more effective types of CME; and to design a survey instrument which can be used to test the applicability of Triandis' model of social behaviour to the provision of CME to general practitioners. METHODS: This was a cross-sectional study on a convenience sample of 11 Australian providers of CME for interviews and a random sample of 25 providers for the pilot test. Open-ended interviews structured on Triandis' theory were performed with key informants who provide CME to GPs. These were used to develop a pilot survey instrument to measure the factors affecting intention, resulting in a revised instrument for use in further research. RESULTS: There was a broad range of factors affecting providers' intention to deliver more effective forms of CME identified, and these were classifiable in a manner which was consistent with Triandis' model. Key factors affecting providers' intention were the attitude toward CME within organisations and the time and extra work involved. CONCLUSIONS: We identified a range of potential factors influencing the intention of providers to provide more effective forms of CME, in all categories of Triandis model. Those interested in increasing the choice of more effective CME activities available to GPs may need to broaden the methods used in working with providers to influence them to use more effective CME techniques. The interview material and questionnaire analysis of the pilot survey support the use of Triandis model. Further research is needed to validate Triandis'model for the intention to deliver more effective forms of CME. Such research will inform future strategies aimed at increasing the amount and choice of effective CME activities available for GPs

Influences of Excluded Volume of Molecules on Signaling Processes on Biomembrane

We investigate the influences of the excluded volume of molecules on biochemical reaction processes on 2-dimensional surfaces using a model of signal transduction processes on biomembranes. We perform simulations of the 2-dimensional cell-based model, which describes the reactions and diffusion of the receptors, signaling proteins, target proteins, and crowders on the cell membrane. The signaling proteins are activated by receptors, and these activated signaling proteins activate target proteins that bind autonomously from the cytoplasm to the membrane, and unbind from the membrane if activated. If the target proteins bind frequently, the volume fraction of molecules on the membrane becomes so large that the excluded volume of the molecules for the reaction and diffusion dynamics cannot be negligible. We find that such excluded volume effects of the molecules induce non-trivial variations of the signal flow, defined as the activation frequency of target proteins, as follows. With an increase in the binding rate of target proteins, the signal flow varies by i) monotonically increasing; ii) increasing then decreasing in a bell-shaped curve; or iii) increasing, decreasing, then increasing in an S-shaped curve. We further demonstrate that the excluded volume of molecules influences the hierarchical molecular distributions throughout the reaction processes. In particular, when the system exhibits a large signal flow, the signaling proteins tend to surround the receptors to form receptor-signaling protein clusters, and the target proteins tend to become distributed around such clusters. To explain these phenomena, we analyze the stochastic model of the local motions of molecules around the receptor.Comment: 31 pages, 10 figure

On the Action of Methotrexate and 6-Mercaptopurine on M. avium Subspecies paratuberculosis

BACKGROUND: Clinical improvement in inflammatory bowel disease (IBD) treated with methotrexate and 6-mercaptopurine (6-MP) is associated with a decrease in pro-inflammatory cytokines. This has been presumed to indicate the mechanism of action of methotrexate and 6-MP. Although controversial, there are increasingly compelling data that Mycobacterium avium subspecies paratuberculosis (MAP) may be an etiological agent in some or all of IBD. We hypothesized that the clinical efficacy of methotrexate and 6-MP in IBD may be to simply inhibit the growth of MAP. METHODOLOGY: The effect on MAP growth kinetics by methotrexate and 6-MP were evaluated in cell culture of two strains each of MAP and M. avium using a radiometric ((14)CO(2) BACTEC®) detection system that quantifies mycobacterial growth as arbitrary “growth index units” (GI). Efficacy data are presented as “percent decrease in cumulative GI” (% −ΔcGI). PRINCIPAL FINDINGS: The positive control antibiotic (clarithromycin) has ≥85% −ΔcGI at a concentration of 0.5 µg/ml. The negative control (ampicillin) has minimal inhibition at 64 µg/ml. MAP ATCC 19698 shows ≥80% −ΔcGI for both agents by 4 µg/ml. With the other three isolates, although more effective than ampicillin, 6-MP is consistently less effective than methotrexate. CONCLUSIONS: We show that methotrexate and 6-MP inhibit MAP growth in vitro. Each of the four isolates manifests different % −ΔcGI. These data are compatible with the hypothesis that the clinical improvement in patients with IBD treated with methotrexate and 6-MP could be due to treating a MAP infection. The decrease in pro-inflammatory cytokines, thought to be the primary mechanism of action, may simply be a normal, secondary, physiological response. We conclude that henceforth, in clinical studies that evaluate the effect of anti-MAP agents in IBD, the use of methotrexate and 6-MP should be excluded from any control groups

Television viewing in Thai infants and toddlers: impacts to language development and parental perceptions

<p>Abstract</p> <p>Background</p> <p>Effects of television to language development in infants and toddlers, especially in the Asian children, are inconclusive. This study aimed to (a) study time spent on television in Thai infants and toddlers (age < 2 years), (b) investigate the association between time spent on television (as recommended by the American Academy of Paediatrics (AAP), < 2 hours per day) and language development in Thai 2-year-old children, and (c) explore parental perceptions on television toward their child's development.</p> <p>Methods</p> <p>Two hundred and sixty children and their parents were recruited into the study. Time spent on television and parental perceptions on television viewing toward their child's development were recorded during face-to-face and telephone interviews. Language development was assessed at the age of 2 years using the Clinical Linguistic Auditory Milestone Scale (CLAMS), and parents' report. Association between delayed language development and time spent on television viewing, as well as other various parameters such as gender, maternal education and family income, were analysed using a multivariate logistic regression model.</p> <p>Results</p> <p>Most Thai infants and toddlers watched television at the age of 6 months, 1 year and 2 years old (98.0, 95.3 and 96.7%, respectively). On average, 1-year-old children watched television 1.23 ± 1.42 hours per day. This increased to 1.69 ± 1.56 hours per day when they were 2 years old. However, watching television longer than 2 hours per day did not associate with delayed language development. On multivariate logistic regression analysis, gender (male) was the only significant factor associated with delayed language development (OR = 6.9, 95% CI = 1.5–31.3). Moreover, 75%, 71%, and 66% of Thai parents believed that television viewing yielded benefits to children's developments.</p> <p>Conclusion</p> <p>Thai children commenced watching television at an early age and the amount of television viewing time increased by age. Most parents had positive perceptions to television viewing. The study found no association between time spent on television viewing (≥ 2 hours per day) and delayed language development at the age of 2 years.</p> <p>Gender (male) was the only variable associated with delayed language development.</p

External Evaluation of a Gentamicin Infant Population Pharmacokinetic Model Using Data from a National Electronic Health Record Database

Gentamicin is a common antibiotic used in neonates and infants. A recently published population pharmacokinetic (PK) model was developed using data from multiple studies, and the objective of our analyses is to evaluate the feasibility of using a national electronic health record (EHR) database to further externally evaluate this model. Our results suggest that with proper data capture procedures, EHR data can serve as a potential data source for external evaluation of PK models

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.

OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012." DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality

Human Mas-related G protein-coupled receptors-X1 induce chemokine receptor 2 expression in rat dorsal root ganglia neurons and release of chemokine ligand 2 from the human LAD-2 mast cell line

Primate-specific Mas-related G protein-coupled receptors-X1 (MRGPR-X1) are highly enriched in dorsal root ganglia (DRG) neurons and induce acute pain. Herein, we analyzed effects of MRGPR-X1 on serum response factors (SRF) or nuclear factors of activated T cells (NFAT), which control expression of various markers of chronic pain. Using HEK293, DRG neuron-derived F11 cells and cultured rat DRG neurons recombinantly expressing human MRGPR-X1, we found activation of a SRF reporter gene construct and induction of the early growth response protein-1 via extracellular signal-regulated kinases-1/2 known to play a significant role in the development of inflammatory pain. Furthermore, we observed MRGPR-X1-induced up-regulation of the chemokine receptor 2 (CCR2) via NFAT, which is considered as a key event in the onset of neuropathic pain and, so far, has not yet been described for any endogenous neuropeptide. Up-regulation of CCR2 is often associated with increased release of its endogenous agonist chemokine ligand 2 (CCL2). We also found MRGPR-X1-promoted release of CCL2 in a human connective tissue mast cell line endogenously expressing MRGPR-X1. Thus, we provide first evidence to suggest that MRGPR-X1 induce expression of chronic pain markers in DRG neurons and propose a so far unidentified signaling circuit that enhances chemokine signaling by acting on two distinct yet functionally co-operating cell types. Given the important role of chemokine signaling in pain chronification, we propose that interruption of this signaling circuit might be a promising new strategy to alleviate chemokine-promoted pain

Age-related changes in global motion coherence: conflicting haemodynamic and perceptual responses

Our aim was to use both behavioural and neuroimaging data to identify indicators of perceptual decline in motion processing. We employed a global motion coherence task and functional Near Infrared Spectroscopy (fNIRS). Healthy adults (n = 72, 18-85) were recruited into the following groups: young (n = 28, mean age = 28), middle-aged (n = 22, mean age = 50), and older adults (n = 23, mean age = 70). Participants were assessed on their motion coherence thresholds at 3 different speeds using a psychophysical design. As expected, we report age group differences in motion processing as demonstrated by higher motion coherence thresholds in older adults. Crucially, we add correlational data showing that global motion perception declines linearly as a function of age. The associated fNIRS recordings provide a clear physiological correlate of global motion perception. The crux of this study lies in the robust linear correlation between age and haemodynamic response for both measures of oxygenation. We hypothesise that there is an increase in neural recruitment, necessitating an increase in metabolic need and blood flow, which presents as a higher oxygenated haemoglobin response. We report age-related changes in motion perception with poorer behavioural performance (high motion coherence thresholds) associated with an increased haemodynamic response