Imaging, Tracking and Computational Analyses of Virus Entry and Egress with the Cytoskeleton.
Viruses have a dual nature: particles are "passive substances" lacking chemical energy transformation, whereas infected cells are "active substances" turning-over energy. How passive viral substances convert to active substances, comprising viral replication and assembly compartments has been of intense interest to virologists, cell and molecular biologists and immunologists. Infection starts with virus entry into a susceptible cell and delivers the viral genome to the replication site. This is a multi-step process, and involves the cytoskeleton and associated motor proteins. Likewise, the egress of progeny virus particles from the replication site to the extracellular space is enhanced by the cytoskeleton and associated motor proteins. This overcomes the limitation of thermal diffusion, and transports virions and virion components, often in association with cellular organelles. This review explores how the analysis of viral trajectories informs about mechanisms of infection. We discuss the methodology enabling researchers to visualize single virions in cells by fluorescence imaging and tracking. Virus visualization and tracking are increasingly enhanced by computational analyses of virus trajectories as well as in silico modeling. Combined approaches reveal previously unrecognized features of virus-infected cells. Using select examples of complementary methodology, we highlight the role of actin filaments and microtubules, and their associated motors in virus infections. In-depth studies of single virion dynamics at high temporal and spatial resolutions thereby provide deep insight into virus infection processes, and are a basis for uncovering underlying mechanisms of how cells function.


Securing funds for health promotion: lessons from health promotion foundations based on experiences from Austria, Australia, Germany, Hungary and Switzerland.
Worldwide, countries face the challenge of securing funds for health promotion. To address this issue, some governments have established health promotion foundations, which are statutory bodies with long-term and recurrent public resources. This article draws on experiences from Austria, Australia, Germany, Hungary and Switzerland to illustrate four lessons learned from the foundation model to secure funding for health promotion. These lessons are concerned with: (i) the broad spectrum of potential revenue sources for health promotion foundations within national contexts; (ii) legislative anchoring of foundation revenues as a base for financial sustainability; (iii) co-financing as a means to increase funds and shared commitment for health promotion; (iv) complementarity of foundations to existing funding. Synthesizing the lessons, we discuss health promotion foundations in relation to wider concerns for investment in health based on the values of sustainability, solidarity and stewardship. We recommend policy-makers and researchers take notice of health promotion foundations as an alternative model for securing funds for health promotion, and appreciate their potential for integrating inter-sectoral revenue collection and inter-sectoral funding strategies. However, health promotion foundations are not a magic bullet. They also pose challenges to coordination and public sector stewardship. Therefore, health promotion foundations will need to act in concert with other governance instruments as part of a wider societal agenda for investment in health.


Expression of ErbB3, ErbB4, and neuregulin-1 mRNA during tooth development.
The receptor tyrosine kinases ErbB3 and ErbB4, which bind to various variants of neuregulin (NRG), play fundamental roles in neural development and in organs, which form through epithelial-mesenchymal interactions. Here, we demonstrate that NRG-1 and the receptors ErbB3 and ErbB4 are expressed locally during rodent tooth development. However, the mRNA expression patterns of ErbB3 and ErbB4 were distinctly different during odontogenesis. Examinations of teeth in genetically heart-rescued ErbB4-/- mice did not reveal any obvious deviation from the normal phenotype. The results suggest that ErbB3 and ErbB4 may participate in tooth morphogenesis. The specific interactions between NRG isoforms and ErbB receptors during this process remain to be determined.


Contrast material extravasation on contrast-enhanced helical computed tomographic scan of blunt abdominal trauma: its significance on the choice, time, and outcome of treatment.
Contrast-enhanced helical computed tomographic (CT) scan of blunt abdominal trauma is valuable for detecting contrast material extravasation (CME). The aims of this study were to determine its significance and investigate factors associated with the choice, time, and outcome of management. CT scans of 32 consecutive trauma patients who had CME were reviewed for the sources of CME, types of CME, flat inferior vena cava, and multiple abdominal injuries. The medical records were reviewed for demographics, systolic blood pressure, Injury Severity Score (ISS), choice of management, time interval between CT scan and intervention, and outcome of intervention. Systolic blood pressure < 100 mm Hg was the most important factor (p = 0.0064) that failed observational therapy. When proceeding to intervention treatment, patients with a flat inferior vena cava (1.6 +/- 1.1 hours) had a significantly shorter time interval between CT scan examination and intervention when compared with those with a normal cava (10.9 +/- 16.0 hours) ( p= 0.0124). The mortality rate after intervention treatment was 18.8%. High ISS, uncontained CME in the extraperitoneum, and multiple abdominal injuries were important risk factors. After adjusted for ISS and multiple abdominal injuries, the risk of dying from extraperitoneal CME remained significant when compared with intraperitoneal CME (adjusted odds ratio, 82.26; 95% confidence interval, 1.06-6,363.17). Termination of observational therapy was appropriate for trauma patients who had CME and systolic blood pressure < 100 mm Hg. The coexistence of a flat inferior vena cava and CME was associated with early intervention treatment. Despite early intervention, the mortality rate was 18.8%. High ISS and multiple abdominal injuries were important factors, but the risk of dying from uncontained extraperitoneal CME was 82 times the risk of dying from intraperitoneal CME.


Antidiabetic effect of hydroalcholic urticadioica leaf extract in male rats with fructose-induced insulin resistance.
Urtica dioica has been used as antihypertensive, antihyperlipidemic and antidiabetic herbal medicine. The purpose of this study was to study the effect of hydroalcoholic extract of Urtica dioica on fructose-induced insulin resistance rats. Forty male Wistar rats were randomly divided into five groups including control, fructose, extract 50, extract 100 and extract 200. The control rat received vehicle, the fructose and extract groups received fructose 10% for eight weeks. The extract groups received single daily injection of vehicle, 50, 100 or 200 mg/kg/day for the two weeks. Blood glucose, insulin, last fasting insulin resistance index (FIRI), serum triglyceride (TG), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), high-density lipoprotein (HDL), alanin trasaminase (AST) and alkaline phosphatase (ALP), leptin and LDL/HDL ratio were determined. Compared to control group, daily administration of fructose was associated with significant increase in FIRI, blood glucose and insulin, significant decrease in lepin, and no significant change in TG, HDL, LDL, LDL/HDL ratio, VLDL, ALT, and ALP. The extract significantly decreased serum glucose, insulin, LDL and leptin, and LDL/HDL ratio and FIRI. It also significantly increased serum TG, VLDL, and AST, but did not change serum ALP. We suggest that Urtica dioica extract, by decreasing serum glucose, and FIRI, may be useful to improve type 2 diabetes mellitus. Also, by positive effect on lipid profile and by decreasing effect on leptin, it may improve metabolic syndrome.


Personality features and vulnerability to stress: a case study on hyperhidrosis.
By using the Rorschach test, self-reports, and psychophysiological measures, we investigated thoroughly the psychological functioning in a hyperhidrotic case. Erica, a young female with hyperhidrosis, was assessed in three times at one-week distance. First, specific tools assessing potential psychological and affective distress, and the Rorschach test were administered. About one week later, Electrodermal Activity was recorded during the exposure to a mild laboratory stress-inducing task. Finally, a magnetic resonance imaging exam was performed in order to exclude medical conditions/neurological alterations for potential physiological anomalies. Erica tends to avoid living in the moment and prefers to experience close relationships in her inner world where she can rehearse the future and imagine different contexts and social situations without risks and embarrassment. She reports high capacities to perform goaldirected behaviors and clarity of emotions only in absence of stressful situations. The study has the merit to be the first to combine Rorschach data with physiological data in order to investigate the psychological functioning in a hyperhidrotic case.


Unconscious and conscious processing of color rely on activity in early visual cortex: a TMS study.
Chromatic information is processed by the visual system both at an unconscious level and at a level that results in conscious perception of color. It remains unclear whether both conscious and unconscious processing of chromatic information depend on activity in the early visual cortex or whether unconscious chromatic processing can also rely on other neural mechanisms. In this study, the contribution of early visual cortex activity to conscious and unconscious chromatic processing was studied using single-pulse TMS in three time windows 40-100 msec after stimulus onset in three conditions: conscious color recognition, forced-choice discrimination of consciously invisible color, and unconscious color priming. We found that conscious perception and both measures of unconscious processing of chromatic information depended on activity in early visual cortex 70-100 msec after stimulus presentation. Unconscious forced-choice discrimination was above chance only when participants reported perceiving some stimulus features (but not color).


Fiber-optic evanescent-wave spectroscopy for fast multicomponent analysis of human blood.
A spectral analysis of human blood serum was undertaken by fiber-optic evanescent-wave spectroscopy (FEWS) by the use of a Fourier-transform infrared spectrometer. A special cell for the FEWS measurements was designed and built that incorporates an IR-transmitting silver halide fiber and a means for introducing the blood-serum sample. Further improvements in analysis were obtained by the adoption of multivariate calibration techniques that are already used in clinical chemistry. The partial least-squares algorithm was used to calculate the concentrations of cholesterol, total protein, urea, and uric acid in human blood serum. The estimated prediction errors obtained (in percent from the average value) were 6% for total protein, 15% for cholesterol, 30% for urea, and 30% for uric acid. These results were compared with another independent prediction method that used a neural-network model. This model yielded estimated prediction errors of 8.8% for total protein, 25% for cholesterol, and 21% for uric acid.


Alternatively spliced forms of the alpha subunit of the epithelial sodium channel: distinct sites for amiloride binding and channel pore.
The amiloride-sensitive epithelial sodium channel (ENAC) consists of at least three subunits, alpha, beta, and gamma. Sodium conductance occurs when only the alpha subunit is expressed in Xenopus oocytes, but it is greatly enhanced by coexpression of all three subunits. All three subunits have two transmembrane domains. Whether the amiloride binding site exists in the extracellular portion or a transmembrane domain has not been established. Using reverse transcription-polymerase chain reaction in rat taste tissues, we have identified two alternatively spliced transcripts of ENAC (alpha ENACa and alpha ENACb) with deletions of nucleotides that introduce a premature stop codon and may result in proteins shortened by 199 and 216 amino acids, respectively, at the carboxyl terminus. Genomic Southern blots indicate that a single gene accounts for alpha ENAC and the alternatively spliced variants. Reverse transcription-polymerase chain reaction and RNase protection assays demonstrate that alpha ENACa is expressed to a lesser extent than alpha ENAC in kidney, lung, and taste tissues. alpha ENACa differs from alpha ENAC by a deletion in the second transmembrane domain. Despite this deletion, alpha ENACa expression in transfected human embryonic kidney 293 cells or CV-1 cells augments [3H]phenamil binding. The [3H]phenamil binding of alpha ENACa resembles that of alpha ENAC, being inhibited more potently by phenamil (Kd = 65 nM) than amiloride. Unlike alpha ENAC, expression of alpha ENACa in Xenopus oocytes fails to generate amiloride-sensitive Na+ or Li+ currents. These results suggest that the amiloride binding site resides on the extracellular loop of the alpha subunit of ENAC and not the putative second transmembrane domain, which forms a channel pore. Heterogeneity in alpha ENAC isoforms may contribute to the complexity of multimeric structures and functional variation of ENAC.


Informed consent as a form of volunteer bias.
Two nontreatment studies of tardive dyskinesia were examined to see if giving or refusing informed consent might bias results. Three prominent psychiatric journals were also reviewed to determine whether the outcome of informed consent procedures was sufficiently well described to permit evaluation of potential bias. The nontreatment studies suggested that the bias created by requiring informed consent may cause both false-positive and false-negative findings. The literature review showed that treatment studies have generally ignored the potential impact of these biases on results. Accurate interpretation of research reports, particularly clinical trials, demands that more attention be given to the process of obtaining and reporting informed consent.


The contents of adenine nucleotides, phosphagens and some glycolytic intermediates in resting muscles from vertebrates and invertebrates.
The lowest contents of ATP and the lowest ATP/AMP concentration ratios are observed in the molluscan muscles that have very low rates of energy expenditure during contraction. The highest contents of ATP are observed in the extremely aerobic insect flight muscle and the extremely anaerobic pectoral muscle of the pheasant and domestic fowl. In general, the lowest ATP/AMP concentration ratios are observed for muscle in which the variation in the rate of energy utilization is small (e.g. some molluscan muscles, heart muscle); the highest ratios are observed in muscles in which this variation is large (lobster abdominal muscle, pheasant pectoral muscle, some insect flight muscles). This finding is consistent with the proposed role of AMP and the adenylate kinase reaction in the regulation of glycolysis. However, in the flight muscle of the honey-bee the ATP/AMP ratio is very low, so that glycolysis may be regulated by factors other than the variation in AMP concentration. The variation in the contents of arginine phosphate in muscle from the invertebrates is much larger than the variation in creatine phosphate in muscle from the vertebrates. The contents of hexose monophosphates and pyruvate are, in general, higher in the muscles of vertebrates than in those of the invertebrates. The contents of phosphoenolpyruvate are similar in all the muscles investigated, except for the honey-bee in which it is about 4-10-fold higher. The mass-action ratios for the reactions catalysed by phosphoglucoisomerase and adenylate kinase are very similar to the equilibrium constants for these reactions. Further, the variation in the mass-action ratios between muscles is small. It is concluded that these enzymes catalyse reactions close to equilibrium. However, the mass-action ratios for the reactions catalysed by phosphofructokinase and pyruvate kinase are much smaller than the equilibrium constants. The variation in the ratios between different muscles is large. It is concluded that these enzymes catalyse nonequilibrium reactions. Since the variation in the mass-action ratios for the reactions catalysed by the phosphagen kinases (i.e. creatine and arginine phosphokinases) is small, it is suggested that these reactions are close to equilibrium.


Functional counterparts of mammalian protein kinases PDK1 and SGK in budding yeast.
In animal cells, recruitment of phosphatidylinositol 3-kinase by growth factor receptors generates 3-phosphoinositides, which stimulate 3-phosphoinositide-dependent protein kinase-1 (PDK1). Activated PDK1 then phosphorylates and activates downstream protein kinases, including protein kinase B (PKB)/c-Akt, p70 S6 kinase, PKC isoforms, and serum- and glucocorticoid-inducible kinase (SGK), thereby eliciting physiological responses. We found that two previously uncharacterised genes of Saccharomyces cerevisiae, which we term PKH1 and PKH2, encode protein kinases with catalytic domains closely resembling those of human and Drosophila PDK1. Both Pkh1 and Pkh2 were essential for cell viability. Expression of human PDK1 in otherwise inviable pkh1Delta pkh2Delta cells permitted growth. In addition, the yeast YPK1 and YKR2 genes were found to encode protein kinases each with a catalytic domain closely resembling that of SGK; both Ypk1 and Ykr2 were also essential for viability. Otherwise inviable ypk1Delta ykr2Delta cells were fully rescued by expression of rat SGK, but not mouse PKB or rat p70 S6 kinase. Purified Pkh1 activated mammalian SGK and PKBalpha in vitro by phosphorylating the same residue as PDK1. Pkh1 activated purified Ypk1 by phosphorylating the equivalent residue (Thr504) and was required for maximal Ypk1 phosphorylation in vivo. Unlike PKB, activation of Ypk1 and SGK by Pkh1 did not require phosphatidylinositol 3,4,5-trisphosphate, consistent with the absence of pleckstrin homology domains in these proteins. The phosphorylation consensus sequence for Ypk1 was similar to that for PKBalpha and SGK. Pkh1 and Pkh2 function similarly to PDK1, and Ypk1 and Ykr2 to SGK. As in animal cells, these two groups of yeast kinases constitute two tiers of a signalling cascade required for yeast cell growth.


Establishing a legal service for major trauma patients at a major trauma centre in the UK.
Major trauma causes unanticipated critical illness and patients have often made few arrangements for what are sudden and life-changing circumstances. This can lead to financial, housing, insurance, legal and employment issues for patients and their families.A UK law firm worked with the major trauma services to develop a free and comprehensive legal service for major trauma patients and their families at a major trauma centre (MTC) in the UK. In 2013, a legal service was established at North Bristol NHS Trust. Referrals are made by trauma nurse practitioners and it operates within a strict ethical framework. A retrospective analysis of the activity of this legal service between September 2013 and October 2015 was undertaken. 66 major trauma patients were seen by the legal teams at the MTC. 535 hours of free legal advice were provided on non-compensation issues-an average of 8 hours per patient. This initiative confirms a demand for the early availability of legal advice for major trauma patients to address a range of non-compensation issues as well as for identification of potential compensation claims. The availability of advice at the MTC is convenient for relatives who may be spending the majority of their time with injured relatives in hospital. More data are needed to establish the rehabilitation and health effects of receiving non-compensation advice after major injury; however, the utilisation of this service suggests that it should be considered at the UK MTCs.


Structure of the FP domain of Fbxo7 reveals a novel mode of protein-protein interaction.
The FP (Fbxo7/PI31) domains found in the F-box protein Fbxo7 and the proteasome inhibitor PI31 mediate the homodimerization and heterodimerization of Fbxo7 and PI31. Fbxo7 is the substrate-recognition subunit of the SCF(Fbxo7) (Skp1-Cul1-F-box protein) E3 ubiquitin ligase that catalyzes the ubiquitination of hepatoma up-regulated protein (HURP) and inhibitor of apoptosis protein (IAP). Fbxo7 also interacts with proteins that are not substrates of the ubiquitin proteasome system, such as Cdk6 and PI31. Here, the crystal structure of the Fbxo7 FP domain is reported at 2.0 Å resolution. The Fbxo7 FP domain adopts an α/β-fold similar to that of the PI31 FP domain. However, an α-helix and three β-strands in the Fbxo7 FP domain are longer than their counterparts in the PI31 FP domain. The differences in these secondary-structural elements are spatially clustered to define a more structured and extended C-terminal end of the Fbxo7 FP domain. The two FP domains also differ substantially in the length and conformation of the longest connecting loop. More importantly, structural differences between the two FP domains lead to drastically different modes of inter-domain protein-protein interaction. The inter-domain interface of the Fbxo7 FP domain is defined by the α-helical surface in one protomer and the β-sheet surface in the other protomer, whereas for the PI31 domain it is defined by either the α-helical surfaces or the β-sheet surfaces in both protomers. The inter-domain interaction of the Fbxo7 FP domain is much more extensive, featuring a larger contact surface area, better shape complementarity and more hydrophobic and hydrogen-bonding interactions. The Fbxo7 FP domain also has the potential to bind two protein partners simultaneously using the α-helical and β-sheet surfaces. The results of this structural study provide critical insights into how Fbxo7 may dimerize (or multimerize) and interact with other regulatory proteins via the FP domain.


Association of Nutritional Factors with Hearing Loss.
Hearing loss (HL) is a major public health problem. Nutritional factors can affect a variety of diseases, such as HL, in humans. Thus far, several studies have evaluated the association between nutrition and hearing. These studies found that the incidence of HL was increased with the lack of single micro-nutrients such as vitamins A, B, C, D and E, and zinc, magnesium, selenium, iron and iodine. Higher carbohydrate, fat, and cholesterol intake, or lower protein intake, by individuals corresponded to poorer hearing status. However, higher consumption of polyunsaturated fatty acids corresponded to better hearing status of studied subjects. In addition to malnutrition, obesity was reported as a risk factor for HL. In studies of the relationship between middle ear infection and nutrition in children, it was reported that lack of vitamins A, C and E, and zinc and iron, resulted in poorer healing status due to vulnerability to infection. These studies indicate that various nutritional factors can affect hearing. Therefore, considering that multifactorial nutritional causes are responsible, in part, for HL, provision of proper guidelines for maintaining a proper nutritional status is expected to prevent some of the causes and burden of HL.


Sex Differences in Microglia Activity within the Periaqueductal Gray of the Rat: A Potential Mechanism Driving the Dimorphic Effects of Morphine.
Although morphine remains the primary drug prescribed for alleviation of severe or persistent pain, both preclinical and clinical studies have shown that females require two to three times more morphine than males to produce comparable levels of analgesia. In addition to binding to the neuronal μ-opioid receptor, morphine binds to the innate immune receptor toll-like receptor 4 (TLR4) localized primarily on microglia. Morphine action at TLR4 initiates a neuroinflammatory response that directly opposes the analgesic effects of morphine. Here, we test the hypothesis that the attenuated response to morphine observed in females is the result of increased microglia activation in the periaqueductal gray (PAG), a central locus mediating the antinociceptive effects of morphine. We report that, whereas no overall sex differences in the density of microglia were noted within the PAG of male or female rats, microglia exhibited a more "activated" phenotype in females at baseline, with the degree of activation a significant predictor of morphine half-maximal antinociceptive dose (ED50) values. Priming microglia with LPS induced greater microglia activation in the PAG of females compared with males and was accompanied by increased transcription levels of IL-1β and a significant rightward shift in the morphine dose-response curve. Blockade of morphine binding to PAG TLR4 with (+)-naloxone potentiated morphine antinociception significantly in females such that no sex differences in ED50 were observed. These results demonstrate that PAG microglia are sexually dimorphic in both basal and LPS-induced activation and contribute to the sexually dimorphic effects of morphine in the rat.SIGNIFICANCE STATEMENT We demonstrate that periaqueductal gray (PAG) microglia contribute to the sexually dimorphic effects of morphine. Specifically, we report that increased activation of microglia in the PAG contributes to the attenuated response to morphine observed in females. Our data further implicate the innate immune receptor toll-like receptor 4 (TLR4) as an underlying mechanism mediating these effects and establish that TLR4 inhibition in the PAG of females reverses the sex differences in morphine responsiveness. These data suggest novel methods to improve current opioid-based pain management via inhibition of glial TLR4 and illustrate the necessity for sex-specific research and individualized treatment strategies for the management of pain in men and women.


New plastic formations in the Anthropocene.
Plastic pollution is one of the major challenges in the Anthropocene. Upon reaching the marine environment, plastic debris is subject to anthropogenic and environmental conditions that result in novel items that vary in composition, physical and chemical characteristics. Here, we reviewed and discussed the potential fate and threat to the environment of four recently described plastic formations: Plastiglomerates, pyroplastics, plasticrusts, and anthropoquinas. The threats identified were mostly related to the release of toxic chemicals and plastic ingestion. Transportation of alien invasive species or microbial pathogens and fragmentation of larger plastics into microplastics (<5 mm), potentially reaching marine trophic webs, are suspected as potential impacts based on the characteristics of these plastic formations. Some plastic forms may persist in the environment and voyage across the ocean, while others are denser and less likely to enter the plastic cycle or interact with biota. In the latter case, plastics are expected to become buried in the sediment and incorporate into the geological record. It is necessary to establish sampling protocols or standards that are specific to each plastic formation and start reporting the occurrence of these new plastic categories as such to avoid underestimating plastic pollution in marine environments. It is suggested that monitoring plans include these categories and identify potential sources. Further research must focus on investigating whether the suspected impacts are a matter of concern. In this sense, we have suggested research questions to address the knowledge gaps and have a better understanding of the impacts and distribution of the new plastic forms.


Expression profiling of skeletal muscle following acute and chronic beta2-adrenergic stimulation: implications for hypertrophy, metabolism and circadian rhythm.
Systemic administration of beta-adrenoceptor (beta-AR) agonists has been found to induce skeletal muscle hypertrophy and significant metabolic changes. In the context of energy homeostasis, the importance of beta-AR signaling has been highlighted by the inability of beta(1-3)-AR-deficient mice to regulate energy expenditure and susceptibility to diet induced obesity. However, the molecular pathways and gene expression changes that initiate and maintain these phenotypic modulations are poorly understood. Therefore, the aim of this study was to identify differential changes in gene expression in murine skeletal muscle associated with systemic (acute and chronic) administration of the beta(2)-AR agonist formoterol. Skeletal muscle gene expression (from murine tibialis anterior) was profiled at both 1 and 4 hours following systemic administration of the beta(2)-AR agonist formoterol, using Illumina 46K mouse BeadArrays. Illumina expression profiling revealed significant expression changes in genes associated with skeletal muscle hypertrophy, myoblast differentiation, metabolism, circadian rhythm, transcription, histones, and oxidative stress. Differentially expressed genes relevant to the regulation of muscle mass and metabolism (in the context of the hypertrophic phenotype) were further validated by quantitative RT-PCR to examine gene expression in response to both acute (1-24 h) and chronic administration (1-28 days) of formoterol at multiple timepoints. In terms of skeletal muscle hypertrophy, attenuation of myostatin signaling (including differential expression of myostatin, activin receptor IIB, phospho-Smad3 etc) was observed following acute and chronic administration of formoterol. Acute (but not chronic) administration of formoterol also significantly induced the expression of genes involved in oxidative metabolism, including hexokinase 2, sorbin and SH3 domain containing 1, and uncoupling protein 3. Interestingly, formoterol administration also appeared to influence some genes associated with the peripheral regulation of circadian rhythm (including nuclear factor interleukin 3 regulated, D site albumin promoter binding protein, and cryptochrome 2). This is the first study to utilize gene expression profiling to examine global gene expression in response to acute beta(2)-AR agonist treatment of skeletal muscle. In summary, systemic administration of a beta(2)-AR agonist had a profound effect on global gene expression in skeletal muscle. In terms of hypertrophy, beta(2)-AR agonist treatment altered the expression of several genes associated with myostatin signaling, a previously unreported effect of beta-AR signaling in skeletal muscle. This study also demonstrates a beta(2)-AR agonist regulation of circadian rhythm genes, indicating crosstalk between beta-AR signaling and circadian cycling in skeletal muscle. Gene expression alterations discovered in this study provides insight into many of the underlying changes in gene expression that mediate beta-AR induced skeletal muscle hypertrophy and altered metabolism.


Aerobic exercise alleviates depressive symptoms in patients with a major non-communicable chronic disease: a systematic review and meta-analysis.
To assess whether aerobic exercise was superior to usual care in alleviating depressive symptoms in patients living with a major non-communicable disease. Data were obtained from online databases (PubMed, PsycINFO and SPORTDiscus) as well as from reference lists. The search and collection of eligible studies was conducted up to 18 October 2018 (PROSPERO registration number CRD42017069089). We included interventions that compared aerobic exercise with usual care in adults who reported depressive symptoms (ie, not necessarily the clinical diagnosis of depression) and were living with a major non-communicable disease. Twenty-four studies were included in the meta-analysis (4111 patients). Aerobic exercise alleviated depressive symptoms better than did usual care (standardised mean difference (SMD)=0.50; 95% CI 0.25 to 0.76; Grading of Recommendations Assessment, Development and Evaluation: low quality). Aerobic exercise was particularly effective in alleviating depressive symptoms in cardiac patients (SMD=0.67; 95% CI 0.35 to 0.99). Aerobic exercise alleviated depressive symptoms in patients living with a major non-communicable disease, particularly in cardiac populations. Whether aerobic exercise treats clinically diagnosed depression was outside the scope of this study.


Bioactive triterpenoids from Kadsura heteroclita.
A phytochemical study of Kadsura heteroclita led to the isolation of eight triterpenoids, including two new compounds, named kadheterilactone A (1) and kadheterilactone B (2), as well as six known compounds, longipedlactone H (3), longipedlactone A (4), longipedlactone F (5), kadsuranic acid A (6), nigranoic acid (7), and schisandronic acid (8). Their structures were elucidated on the basis of spectroscopic methods, including 2D NMR techniques. The cytotoxic activities of 1-8 were tested against several tumor cell lines by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium hydrobromide (MTT) assay in vitro. As a result, 4 and 5 turned out to be significantly cytotoxic against Hep-G2 and Bel-7402 tumor cell lines. All compounds were also tested for inhibition on HIV-1 protease (PR) and reverse transcriptase (RT). Compounds 6 and 7 showed strong inhibition on HIV-1 PR, while 8 exhibited moderate activity, others were only weakly active. No compounds were active against HIV-1 RT.


Endothelial cell capture of heparin-binding growth factors under flow.
Circulation is an important delivery method for both natural and synthetic molecules, but microenvironment interactions, regulated by endothelial cells and critical to the molecule's fate, are difficult to interpret using traditional approaches. In this work, we analyzed and predicted growth factor capture under flow using computer modeling and a three-dimensional experimental approach that includes pertinent circulation characteristics such as pulsatile flow, competing binding interactions, and limited bioavailability. An understanding of the controlling features of this process was desired. The experimental module consisted of a bioreactor with synthetic endothelial-lined hollow fibers under flow. The physical design of the system was incorporated into the model parameters. The heparin-binding growth factor fibroblast growth factor-2 (FGF-2) was used for both the experiments and simulations. Our computational model was composed of three parts: (1) media flow equations, (2) mass transport equations and (3) cell surface reaction equations. The model is based on the flow and reactions within a single hollow fiber and was scaled linearly by the total number of fibers for comparison with experimental results. Our model predicted, and experiments confirmed, that removal of heparan sulfate (HS) from the system would result in a dramatic loss of binding by heparin-binding proteins, but not by proteins that do not bind heparin. The model further predicted a significant loss of bound protein at flow rates only slightly higher than average capillary flow rates, corroborated experimentally, suggesting that the probability of capture in a single pass at high flow rates is extremely low. Several other key parameters were investigated with the coupling between receptors and proteoglycans shown to have a critical impact on successful capture. The combined system offers opportunities to examine circulation capture in a straightforward quantitative manner that should prove advantageous for biologicals or drug delivery investigations.


Induction of transplantation tolerance-the potential of regulatory T cells.
Solid organ transplantation is widely accepted as an effective treatment for end organ failure. Although the treatment with immunosuppressive drugs has undoubtedly greatly improved graft survival, chronic rejection still has considerable impact on long term outcome. This, together with the undesirable side effects associated with life long treatment with immunosuppressive drugs, have significant implications for long term outcomes. In a small number of patients, drug non-compliance as well as controlled reduction or removal of maintenance immune suppressive drug therapy has led to the uncovering of a tolerant state. The challenge of achieving improved monitoring of all transplant patients may allow tailoring of immunosupression in a proportion of recipients thereby increasing the opportunities for the induction of specific unresponsiveness to donor alloantigens in the future. The immune system using several mechanisms to both induce and maintain tolerance to alloantigens, including the deletion of allo-reactive T cells, the induction of anergy, clonal exhaustion, ignorance and active suppression (immunoregulation) of allo-responses. A minor subpopulation of CD4+ T cells, regulatory or suppressor CD4+ T cells that co-express the cell-surface molecule CD25 (IL2 alpha subunit) at a high level may play a major role in the maintenance of specific unresponsiveness and operational tolerance to donor antigens in vivo. Intensive investigation of these cells in recent years has started to uncover the mechanisms of active suppression by regulatory T cells in this setting.


Antimicrobial prevention of early-onset group B streptococcal sepsis: estimates of risk reduction based on a critical literature review.
To identify interventions that reduce the attack rate for early-onset group B streptococcal (GBS) sepsis in neonates. Literature review and reanalysis of published data. The rate of early-onset GBS sepsis in high-risk neonates can be reduced by administration of antibiotics. Treatment during pregnancy (antepartum prophylaxis) fails to reduce maternal GBS colonization at delivery. With the administration of intravenous ampicillin, the risk of early-onset infection in infants born to women with preterm premature rupture of membranes is reduced by 56% and the risk of GBS infection is reduced by 36%; addition of gentamicin may increase the efficacy of ampicillin. Treatment of women with chorioamnionitis with ampicillin and gentamicin during labor reduces the likelihood of neonatal sepsis by 82% and reduces the likelihood of GBS infection by 86%. Universal administration of penicillin to neonates shortly after birth (postpartum prophylaxis) reduces the early-onset GBS attack rate by 68% but is associated with a 40% increase in overall mortality and therefore is contraindicated. Intrapartum prophylaxis, alone or combined with postnatal prophylaxis for the infants, reduces the early-onset GBS attack rate by 80% or 95%, respectively. Women with chorioamnionitis or premature rupture of membranes and their infants should be treated with intravenous ampicillin and gentamicin. Intrapartum antimicrobial prophylaxis may be appropriate for other women whose infants are at increased but less extreme risk, and supplemental postpartum prophylaxis may be indicated for some of their infants. Selection of appropriate candidates and prophylaxis strategies requires careful consideration of costs and benefits for each patient. group B streptococcus, neonatal sepsis, early-onset sepsis, prevention, prophylaxis.


Does Telephone Audio Computer-Assisted Self-Interviewing Improve the Accuracy of Prevalence Estimates of Youth Smoking? Evidence from the UMass Tobacco Study.
Despite their advantage for obtaining representative samples of adolescents, telephone surveys have been regarded as inferior for collecting data on youth tobacco use because they yield lower estimates than school-based self-administered surveys. Although no gold standard for smoking estimates exists, the lower estimates in telephone surveys have been attributed to underreporting due to youths' concern about parents or others overhearing their responses. Telephone audio computer-assisted self-interviewing (T-ACASI) is a cost-effective method for obtaining a representative sample of youths and provides increased privacy for the respondent. We hypothesized that using T-ACASI would encourage youths to more fully report smoking behavior compared to traditional interviewer-administered telephone methods. Our analysis further assessed whether respondent age, gender, race/ethnicity, and parental attitude toward smoking moderated the relationship between survey mode and smoking reports. Using data from a statewide tobacco use survey that randomly assigned youth respondents to either T-ACASI or interviewer-administered mode, we found youths were more likely to report smoking behaviors in T-ACASI mode and that this was especially true for girls, particularly those who believed their parents would disapprove strongly of their smoking. Findings suggest that traditional telephone surveys may underestimate smoking prevalence in most girls by a factor of two, and that a technique for insuring privacy for these respondents is an important component of effective telephone survey methodology.


Effects of ear acupuncture therapy for obesity on the depression of obese women.
Obesity is one of the leading health risks worldwide, and depression is among the leading causes of the burden of disease. These disorders are increasingly prevalent as comorbidities. Depressive symptoms are associated with obesity, and are more common in women. To evaluate the effectiveness of ear acupuncture for obesity on the depression of obese women. After baseline testing, 30 eligible patients with body mass index (BMI) >29.9 kg/m(2) were included. The Beck Depression Inventory for Primary Care (BDI-PC) was used to assess changes in depression. BMI was also measured. Patients had six ear acupuncture sessions, every 15 days and were followed up for 3 months. Twenty four patients completed the study. The mean±SD age of patients was 42.9±9.0 years. Their mean±SD BMI was 39.0±4.7 kg/m(2) before acupuncture, decreasing to 37.2±4.3 kg/m(2) after acupuncture therapy (p<0.001). The mean depression score was 4.4±2.3 before acupuncture, decreasing to 2.7±1.4 (p<0.001) after treatment. There was no significant correlation between BMI and depression score before acupuncture therapy (p=0.104). After acupuncture therapy, no significant correlation was found between the percentage reduction of BMI and percentage reduction of the depression score (p=0.119). Further research into the effects of ear acupuncture in the management of obesity and depression is justified.


Effects of Linagliptin on Cardiovascular and Kidney Outcomes in People With Normal and Reduced Kidney Function: Secondary Analysis of the CARMELINA Randomized Trial.
Type 2 diabetes is a leading cause of kidney failure, but few outcome trials proactively enrolled individuals with chronic kidney disease (CKD). We performed secondary analyses of cardiovascular (CV) and kidney outcomes across baseline estimated glomerular filtration rate (eGFR) categories (≥60, 45 to <60, 30 to <45, and <30 mL/min/1.73 m2) in Cardiovascular and Renal Microvascular Outcome Study With Linagliptin (CARMELINA), a cardiorenal placebo-controlled outcome trial of the dipeptidyl peptidase 4 inhibitor linagliptin (NCT01897532). Participants with CV disease and/or CKD were included. The primary outcome was time to first occurrence of CV death, nonfatal myocardial infarction, or nonfatal stroke (three-point major adverse CV event [3P-MACE]), with a secondary outcome of renal death, end-stage kidney disease, or sustained ≥40% decrease in eGFR from baseline. Other end points included progression of albuminuria, change in HbA1c, and adverse events (AEs) including hypoglycemia. A total of 6,979 subjects (mean age 65.9 years; eGFR 54.6 mL/min/1.73 m2; 80.1% albuminuria) were followed for 2.2 years. Across eGFR categories, linagliptin as compared with placebo did not affect the risk for 3P-MACE (hazard ratio 1.02 [95% CI 0.89, 1.17]) or the secondary kidney outcome (1.04 [0.89, 1.22]) (interaction P values >0.05). Regardless of eGFR, albuminuria progression was reduced with linagliptin, as was HbA1c, without increasing risk for hypoglycemia. AEs were balanced among groups overall and across eGFR categories. Across all GFR categories, in participants with type 2 diabetes and CKD and/or CV disease, there was no difference in risk for linagliptin versus placebo on CV and kidney events. Significant reductions in risk for albuminuria progression and HbA1c and no difference in AEs were observed.


Some frontiers in social science.
The fundamental challenge in the social sciences is moving from complicated correlations to useful prediction. Progress usually reflects an interplay between theory, data, and tools. Six areas of innovation, principally data and tools, are now pushing at the frontiers of these sciences: longitudinal data, laboratory experimentation, improved statistical methods, geographic information tools, biosocial science, and international replication. These innovations are gaining power as they cross disciplinary boundaries, helping to attribute causality to observed relationships, to understand their nature, and thereby to improve the accuracy and usefulness of predictions.


Telomere shortening as genetic risk factor of liver cirrhosis.
Cirrhosis is the main complication of chronic liver disease, leads to progressive liver function impairment and is the main risk factor for the development of liver cancer. Liver failure at endstage cirrhosis is associated with increased mortality with liver transplantation as the only possible treatment at this stage. The pathogenesis of liver cirrhosis is not completely elucidated. Although the common factors leading to liver injury, such as viral hepatitis, alcohol consume or fatty liver disease can be identified in the majority of patients a small percentage of patients have no apparent risk factors. Moreover given the same risk factors, some patients progress to cirrhosis whereas others have a benign course, the reason remains unclear. In order to develop new diagnostic and therapeutic tools, it is s essential to understand the pathogenesis of cirrhosis. The identification of genetic risk factors associated with cirrhosis is one of the possible approach to achieve these goal. In the past years several studies have supported the role of telomere shortening and cirrhosis. In the recent year several studies on the relation between several single nucleotide polymorphism (SNPs) and cirrhosis have been published; it has been proposed also a cirrhosis risk score based on seven SNPs. Also epidemiological studies on identical twins and in different ethnic groups have been supporting the importance of the role of genetic risk factors. Finally in the very recent years it has been suggested that telomere shortening may represent a genetic risk factor for the development of cirrhosis.


Kefir fermented milk and kefiran promote growth of Bifidobacterium bifidum PRL2010 and modulate its gene expression.
Bifidobacteria constitute one of the dominant groups of microorganisms colonizing the human gut of infants. Their ability to utilize various host-derived glycans as well as dietary carbohydrates has received considerable scientific attention. However, very little is known about the role of fermented foods, such as kefir, or their constituent glycans, such as kefiran, as substrates for bifidobacterial growth and for the modulation of the expression of bifidobacterial host-effector molecules. Here, we show that Bifidobacterium bifidum PRL2010 exhibits high growth performance among the bifidobacterial strains tested when cultivated on kefir and/or kefiran polymer. Furthermore, a 16S rRNA metagenomic approach revealed that the microbiota of kefir is modified upon the addition of PRL2010 cells to the kefir matrix. Finally, our results show that kefir and kefiran are able to influence the transcriptome of B. bifidum PRL2010 causing increased transcription of genes involved in the metabolism of dietary glycans as well as genes that act as host-microbe effector molecules such as pili. Altogether, these data support the use of kefir as a valuable means for the delivery of effective microbial cells in probiotic therapy.


A NIR rhodamine fluorescent chemodosimeter specific for glutathione: Knoevenagel condensation, detection of intracellular glutathione and living cell imaging.
A new near-infrared probe for detecting glutathione based on conjugate addition and intramolecular amino induced spirolactam opening named RhAN was designed and synthesized. Firstly, rhodamine was reacted with 2-(1,3,3-trimethylindolin-2-ylidene) acetaldehyde by a Knoevenagel condensation, and the conjugate chain was extended, obtaining M2. Then, M2 was connected with hydrazide to get M3. Finally, the target molecule RhAN was synthesized via the combination of M3 and acryloyl chloride. In the presence of GSH, RhAN exhibits high selectivity, which specifically identifies GSH over Cys and Hcy, the color change from yellow to green together with the fluorescence appeared within 5 s, and there was no interference from the presence of other biological thiols and amino acids. The absorption and emission wavelength of the probe RhAN reached 717 nm and 739 nm, the molar extinction coefficient is 4.36 × 104 M-1 cm-1 and quantum yield is 0.26. Its absorption and emission intensity were enhanced by more than 117-fold and 90-fold upon addition of GSH, respectively. In addition, it also has high sensitivity with a low detection limit of 0.1 μM, which is lower than most previously reported GSH probes. The probe works excellently within a wide pH range of 2-10. Moreover, RhAN was employed for endogenous and exogenous imaging in MCF-7 cells for GSH. MCF-7 cells incubated with RhAN with GSH or blank RhAN all showed significant fluorescence in the red channel, which indicated that the probe could not only detect exogenous GSH, but it also permeated into the cells and reacted with the intracellular GSH. This is an excellent design for a fluorescence sensor, RhAN, as a quick and effective method for detecting excess GSH in living cells, for maintaining the balance of amino acids in the body and ensuring normal life activities.


Overdose rescues by trained and untrained participants and change in opioid use among substance-using participants in overdose education and naloxone distribution programs: a retrospective cohort study.
One approach to preventing opioid overdose, a leading cause of premature, preventable mortality, is to provide overdose education and naloxone distribution (OEND). Two outstanding issues for OEND implementation include 1) the dissemination of OEND training from trained to untrained community members; and 2) the concern that OEND provides active substance users with a false sense of security resulting in increased opioid use. To compare overdose rescue behaviors between trained and untrained rescuers among people reporting naloxone rescue kit use; and determine whether heroin use changed after OEND, we conducted a retrospective cohort study among substance users in the Massachusetts OEND program from 2006 to 2010. We used chi square and t-test statistics to compare the differences in overdose management characteristics among overdoses managed by trained versus untrained participants. We employed Wilcoxon signed rank test to compare median difference among two repeated measures of substance use among participants with drug use information collected more than once. Among 4,926 substance-using participants, 295 trained and 78 untrained participants reported one or more rescues, resulting in 599 rescue reports. We found no statistically significant differences in help-seeking (p = 0.41), rescue breathing (p = 0.54), staying with the victim (p = 0.84) or in the success of naloxone administration (p = 0.69) by trained versus untrained rescuers. We identified 325 OEND participants who had drug use information collected more than once. We found no significant overall change in the number of days using heroin in past 30 days (decreased 38%, increased 35%, did not change 27%, p = 0.52). Among 4926 substance users who participated in OEND, 373(7.6%) reported administering naloxone during an overdose rescue. We found few differences in behavior between trained and untrained overdose rescuers. Prospective studies will be needed to determine the optimal level of training and whether naloxone rescue kits can meet an over-the-counter standard. With no clear evidence of increased heroin use, this concern should not impede expansion of OEND programs or policies that support them.


What Sexual and Gender Minority People Want Researchers to Know About Sexual Orientation and Gender Identity Questions: A Qualitative Study.
Sexual and gender minority (SGM) people-including members of the lesbian, gay, bisexual, transgender, and queer communities-are understudied and underrepresented in research. Current sexual orientation and gender identity (SOGI) questions do not sufficiently engage SGM people, and there is a critical gap in understanding how SOGI questions reduce inclusion and accurate empirical representation. We conducted a qualitative study to answer the question, "For SGM people, what are the major limitations with current SOGI questions?" Focus groups probed reactions to SOGI questions adapted from prior national surveys and clinical best practice guidelines. Questions were refined and presented in semi-structured cognitive interviews. Template analysis using a priori themes guided analysis. There were 74 participants: 55 in nine focus groups and 19 in cognitive interviews. Participants were diverse: 51.3% identified as gender minorities, 87.8% as sexual minorities, 8.1% as Hispanic/Latinx, 13.5% as Black or African-American, and 43.2% as Non-white. Two major themes emerged: (1) SOGI questions did not allow for identity fluidity and complexity, reducing inclusion and representation, and (2) SOGI question stems and answer choices were often not clear as to which SOGI dimension was being assessed. To our knowledge, this represents the largest body of qualitative data studying SGM perspectives when responding to SOGI questions. We present recommendations for future development and use of SOGI measures. Attention to these topics may improve meaningful participation of SGM people in research and implementation of such research within and for SGM communities.


Spectrum of HSPG2 (Perlecan) mutations in patients with Schwartz-Jampel syndrome.
Schwartz-Jampel syndrome (SJS) is a rare autosomal recessive condition defined by the association of myotonia with chondrodysplasia. SJS results from mutations in the HSPG2 gene, which encodes perlecan, a major component of basement membranes. Only eight HSPG2 mutations have been reported in six SJS families. Here, we describe the molecular findings in 23 families (35 patients) with SJS, being one-third of the SJS cases reported in the medical literature. We identified 22 new HSPG2 mutations and unreported polymorphisms. Mutations included nine deletion or insertion (41%), six splice site (27%), five missense (23%), and two nonsense mutations (9%). All but four mutations were private, and we found no evidence for a founder effect. Analyses of HSPG2 messenger RNA (mRNA) and perlecan immunostaining on patients' cells revealed a hypomorphic effect of the studied mutations. They also demonstrated distinct consequences of truncating and missense mutations on perlecan expression as truncating mutations resulted in instability of HSPG2 mRNA through nonsense mRNA-mediated decay, whereas missense mutations involving cysteine residues led to intracellular retention of perlecan, probably due to quality control pathways. Our analyses strengthen the idea that SJS results from hypomorphic mutations of the HSPG2 gene. They also propose tools for its molecular diagnosis and provide new clues for the understanding of its pathophysiology.


A brief review: factors affecting the length of the rest interval between resistance exercise sets.
Research has indicated that multiple sets are superior to single sets for maximal strength development. However, whether maximal strength gains are achieved may depend on the ability to sustain a consistent number of repetitions over consecutive sets. A key factor that determines the ability to sustain repetitions is the length of rest interval between sets. The length of the rest interval is commonly prescribed based on the training goal, but may vary based on several other factors. The purpose of this review was to discuss these factors in the context of different training goals. When training for muscular strength, the magnitude of the load lifted is a key determinant of the rest interval prescribed between sets. For loads less than 90% of 1 repetition maximum, 3-5 minutes rest between sets allows for greater strength increases through the maintenance of training intensity. However, when testing for maximal strength, 1-2 minutes rest between sets might be sufficient between repeated attempts. When training for muscular power, a minimum of 3 minutes rest should be prescribed between sets of repeated maximal effort movements (e.g., plyometric jumps). When training for muscular hypertrophy, consecutive sets should be performed prior to when full recovery has taken place. Shorter rest intervals of 30-60 seconds between sets have been associated with higher acute increases in growth hormone, which may contribute to the hypertrophic effect. When training for muscular endurance, an ideal strategy might be to perform resistance exercises in a circuit, with shorter rest intervals (e.g., 30 seconds) between exercises that involve dissimilar muscle groups, and longer rest intervals (e.g., 3 minutes) between exercises that involve similar muscle groups. In summary, the length of the rest interval between sets is only 1 component of a resistance exercise program directed toward different training goals. Prescribing the appropriate rest interval does not ensure a desired outcome if other components such as intensity and volume are not prescribed appropriately.


THE PRICE AIN'T RIGHT? HOSPITAL PRICES AND HEALTH SPENDING ON THE PRIVATELY INSURED.
We use insurance claims data covering 28% of individuals with employer-sponsored health insurance in the United States to study the variation in health spending on the privately insured, examine the structure of insurer-hospital contracts, and analyze the variation in hospital prices across the nation. Health spending per privately insured beneficiary differs by a factor of three across geographic areas and has a very low correlation with Medicare spending. For the privately insured, half of the spending variation is driven by price variation across regions, and half is driven by quantity variation. Prices vary substantially across regions, across hospitals within regions, and even within hospitals. For example, even for a nearly homogeneous service such as lower-limb magnetic resonance imaging, about a fifth of the total case-level price variation occurs within a hospital in the cross section. Hospital market structure is strongly associated with price levels and contract structure. Prices at monopoly hospitals are 12% higher than those in markets with four or more rivals. Monopoly hospitals also have contracts that load more risk on insurers (e.g., they have more cases with prices set as a share of their charges). In concentrated insurer markets the opposite occurs-hospitals have lower prices and bear more financial risk. Examining the 366 mergers and acquisitions that occurred between 2007 and 2011, we find that prices increased by over 6% when the merging hospitals were geographically close (e.g., 5 miles or less apart), but not when the hospitals were geographically distant (e.g., over 25 miles apart).


Analysis of the bacterial flora in the nasal cavity and the sphenoid sinus mucosa in patients operated on with an endoscopic endonasal transsphenoidal approach.
The aim of this study was to analyze the bacterial flora in the nasal cavity and sphenoid sinus and evaluate the sensitivity of these bacteria to antibiotics that can be used to prevent postoperative meningitis. Bacteria of the preoperative nasal cavity and intraoperative sphenoid sinus mucosa were cultured and analyzed in 40 patients (20 men and 20 women; mean age, 52.2 years) who underwent endoscopic transsphenoidal surgery. The sensitivity of these bacteria to cephalosporin, a representative prophylactic antibiotic, was examined. Staphylococcus epidermidis was the most frequently detected species in both spaces; 24 (38.7%) of 62 isolates in the nasal cavity and 26 (37.1%) of 70 isolates in the sphenoid sinus. In contrast, Corynebacterium species were found mainly in the nasal cavity, and anaerobic bacteria were found only in the sphenoid sinus. Bacteria that were resistant to cephalosporin were found in the nasal cavity in 3.2% of patients and in the sphenoid sinus in 20% of patients. In conclusion, the composition of bacterial flora, including bacteria that are resistant to prophylactic antibiotics, differs between the nasal cavity and the sphenoid sinus.


What's all the noise about developmental stochasticity?
In October 2010, researchers from diverse backgrounds collided at the historic Cumberland Lodge (Windsor, UK) to discuss the role of randomness in cell and developmental biology. Organized by James Briscoe and Alfonso Marinez-Arias, The Company of Biologists' workshop was the latest in a series of meetings aimed at encouraging interdisciplinary interactions between biologists. This aim was reflected in talks at this workshop that ranged from the tissue to the cellular scale, and that integrated experimental and theoretical approaches to examining stochastic behavior in diverse systems.


Genetic relationships among some species groups within the genus Lutzomyia (Diptera: Psychodidae).
Molecular data on Lutzomyia are very scarce, despite the fact that this genus includes all the species involved in the transmission of leishmaniasis in America. We examine the genetic relationships among eight morphologic groups within the Lutzomyia genus and two Brumptomyia species, using nine enzyme loci and the last 285 basepairs of the mitochondrial cytochrome b gene. The structure of the genetic variation among the species analyzed indicated a closer genetic relationship among members of a morphologic group than between members of different groups. The lower levels of variation recorded among these groups compared with that between Brumptomyia and Lutzomyia suggest a subgeneric status for all of these groups, including Psychodopygus. A maximum likelihood tree for the allozyme data and a neighbor-joining consensus tree for the mitochondrial DNA sequences showed a general agreement with morphologic groups, with only minor differences. Nyssomyia, Verrucarum and Micropygomyia formed separate monophyletic groups. Lutzomyia could not be separated from Psathyromyia, and both Migonei species, L. dubitans and L. migonei, grouped in different clades according to the host species they are found on.


SMV1 virus-induced CRISPR spacer acquisition from the conjugative plasmid pMGB1 in Sulfolobus solfataricus P2.
Organisms of the crenarchaeal order Sulfolobales carry complex CRISPR (clustered regularly interspaced short palindromic repeats) adaptive immune systems. These systems are modular and show extensive structural and functional diversity, especially in their interference complexes. The primary targets are an exceptional range of diverse viruses, many of which propagate stably within cells and follow lytic life cycles without producing cell lysis. These properties are consistent with the difficulty of activating CRISPR spacer uptake in the laboratory, but appear to conflict with the high complexity and diversity of the CRISPR immune systems that are found among the Sulfolobales. In the present article, we re-examine the first successful induction of archaeal spacer acquisition in our laboratory that occurred exclusively for the conjugative plasmid pMGB1 in Sulfolobus solfataricus P2 that was co-infected with the virus SMV1 (Sulfolobus monocaudavirus 1). Although we reaffirm that protospacer selection is essentially a random process with respect to the pMGB1 genome, we identified single spacer sequences specific for each of CRISPR loci C, D and E that, exceptionally, occurred in many sequenced clones. Moreover, the same sequence was reproducibly acquired for a given locus in independent experiments, consistent with it being the first protospacer to be selected. There was also a small protospacer bias (1.6:1) to the antisense strand of protein genes. In addition, new experiments demonstrated that spacer acquisition in the previously inactive CRISPR locus A could be induced on freeze-thawing of the infected cells, suggesting that environmental stress can facilitate activation. Coincidentally with spacer acquisition, a mobile OrfB element was deleted from pMGB1, suggesting that interplay can occur between spacer acquisition and transposition.


Evidence for mood-dependent attentional processing in asthma: attentional bias towards health-threat in depressive mood and attentional avoidance in neutral mood.
Attentional biases have been observed in populations with psychological disorders, but have been under-investigated in populations with physical illnesses. This study investigated potential attentional biases in asthma as a function of mood. Asthma (N = 45), and healthy (N = 39) participants were randomly allocated to a depressed or a neutral mood state induction. They completed a visual probe task that measured participants' reaction times to health-threat and neutral pictures and words. Compared to the healthy controls, the asthma group showed attentional bias towards health-threat pictures in depressed mood, and avoidance of health-threat pictures in neutral mood. Attentional biases were found in a group with a physical illness as a function of induced mood. It is suggested that attentional processes in people with physical illness may be important in relation to symptom perception and illness management.


Peer review of the pesticide risk assessment of the active substance kieselgur (diatomaceous earth).
The conclusions of EFSA following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State Austria and co-rapporteur Member State Greece for the pesticide active substance kieselgur (diatomaceous earth) and the considerations as regards the inclusion of the substance in Annex IV of Regulation (EC) No 396/2005 are reported. The context of the peer review was that required by Commission Implementing Regulation (EU) No 844/2012, as amended by Commission Implementing Regulation (EU) No 2018/1659. The conclusions were reached on the basis of the evaluation of the representative uses of kieselgur (diatomaceous earth) as an insecticide and acaricide on stored cereals, empty storage rooms and storage rooms, mills and warehouses (with stored goods). The reliable end points, appropriate for use in regulatory risk assessment, are presented. Missing information identified as being required by the regulatory framework is listed.


Veterinary science student preferences for the source of dog cadavers used in anatomy teaching.
Live animals and cadavers are integral to veterinary education. In the year of this survey (2008), and in at least the five preceding years, cadavers obtained by euthanasia of healthy pound dogs and ex-racing greyhounds were dissected by students, during their veterinary anatomy classes at the University of Queensland School of Veterinary Science. Students may have ethical concerns about this. An alternative approach was to use donated dog cadavers. These are owned pet dogs that have died of natural causes or have been euthanised for medical reasons, and have been donated by their owners for the purposes of veterinary education. Veterinary students at the School were surveyed in 2008, in order to determine their preferences for cadaver source. Data from 406 questionnaires were analysed. Third-year and fifth-year veterinary students were more likely than first-year students to prefer pound-dog/greyhound cadavers over donated cadavers for anatomy dissection (p ≤ 0.002). Between 32% and 45% of the students had no preference for either source of cadaver. These findings are consistent with the hypothesis that veterinary students become more accepting of the euthanasia of unwanted healthy animals for education as they progress through the veterinary programme, in contexts such as the current study. This could occur due to increased acceptance of the euthanasia of healthy animals generally, a decline in moral development, desensitisation, and/or the belief that healthy animal cadavers offer a superior learning experience.


Potential of Plant Alkaloids as Antipyretic Drugs of Future.
Fever or Pyrexia means abnormal rise in body temperature above the usual range of normal in response to a variety of infectious, immunological and neoplastic stimuli. To normalize these febrile conditions, several synthetic agents are in clinical practice such as acetaminophen, ibuprofen, and aspirin. However, they are having many side effects which sometimes challenge their applications. The various sources are under investigation worldwide to overcome issues of unwanted effects and to better therapeutic response. In this scenario botanicals such as alkaloids, the most widely distributed and studied plant secondary metabolites, could effectively produce the molecules with better antipyretic effect and safety profile. The current review deals with 21 isolated alkaloids from 14 plants species having some antipyretic effect in preliminary screening/preclinical studies with the possible mechanism and structural edges. Therefore, these alkaloids of plant origin are candidates for further detail studies to ascertain their mechanism(s) and clinical utility or as lead compounds for future drugs.


Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with Sepsis.
Guidelines currently recommend targeting light sedation with dexmedetomidine or propofol for adults receiving mechanical ventilation. Differences exist between these sedatives in arousability, immunity, and inflammation. Whether they affect outcomes differentially in mechanically ventilated adults with sepsis undergoing light sedation is unknown. In a multicenter, double-blind trial, we randomly assigned mechanically ventilated adults with sepsis to receive dexmedetomidine (0.2 to 1.5 μg per kilogram of body weight per hour) or propofol (5 to 50 μg per kilogram per minute), with doses adjusted by bedside nurses to achieve target sedation goals set by clinicians according to the Richmond Agitation-Sedation Scale (RASS, on which scores range from -5 [unresponsive] to +4 [combative]). The primary end point was days alive without delirium or coma during the 14-day intervention period. Secondary end points were ventilator-free days at 28 days, death at 90 days, and age-adjusted total score on the Telephone Interview for Cognitive Status questionnaire (TICS-T; scores range from 0 to 100, with a mean of 50±10 and lower scores indicating worse cognition) at 6 months. Of 432 patients who underwent randomization, 422 were assigned to receive a trial drug and were included in the analyses - 214 patients received dexmedetomidine at a median dose of 0.27 μg per kilogram per hour, and 208 received propofol at a median dose of 10.21 μg per kilogram per minute. The median duration of receipt of the trial drugs was 3.0 days (interquartile range, 2.0 to 6.0), and the median RASS score was -2.0 (interquartile range, -3.0 to -1.0). We found no difference between dexmedetomidine and propofol in the number of days alive without delirium or coma (adjusted median, 10.7 vs. 10.8 days; odds ratio, 0.96; 95% confidence interval [CI], 0.74 to 1.26), ventilator-free days (adjusted median, 23.7 vs. 24.0 days; odds ratio, 0.98; 95% CI, 0.63 to 1.51), death at 90 days (38% vs. 39%; hazard ratio, 1.06; 95% CI, 0.74 to 1.52), or TICS-T score at 6 months (adjusted median score, 40.9 vs. 41.4; odds ratio, 0.94; 95% CI, 0.66 to 1.33). Safety end points were similar in the two groups. Among mechanically ventilated adults with sepsis who were being treated with recommended light-sedation approaches, outcomes in patients who received dexmedetomidine did not differ from outcomes in those who received propofol. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01739933.).


Cigarette smoking habit does not reduce the benefit from first line trastuzumab-based treatment in advanced breast cancer patients.
Many ErbB2-positive cancers may show intrinsic resistance, and the frequent development of acquired resistance to ErbB-targeted agents represents a substantial clinical problem. The constitutive NF-κB activation in some HER-2/neu positive breast cancer may represent a potential cause of resistance to trastuzumab therapy. Preclinical data revealed that 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the tobacco-specific nitrosamine is able to enhance NF-κB DNA binding activity and theoretically to increase the resistance to trastuzumab. Two hundred and forty-eight women with pathologically confirmed, uni- or bidimensionally measurable, HER-2-positive metastatic breast cancer (MBC) treated with trastuzumab-based therapy as first line combination for metastatic disease were considered eligible. For all included patients data on smoking habit were detectable from medical records. We retrospectively analysed the smoking habits of 248 MBC patients and correlated these habits with activity and efficacy of trastuzumab-based therapy. No statistically significant difference in terms of response rate (RR), time to progression (TTP) and overall survival (OS) was identified between smokers (former plus active smokers) and never smokers. Moreover, no statistically significant difference in terms of RR, TTP and OS was identified either comparing active smokers and former smokers. Moreover, we did not observed any significant statistical difference in terms of TTP and OS between smokers ≥10 cigarettes/day and <10 cigarettes/day. This study clearly showed lack of any correlation between cigarette smoking habit and both activity and efficacy of trastuzumab-based first line therapy in metastatic HER2/neu positive breast cancer patients.


"Change is possible": Patients' experience of a multimodal chronic pain rehabilitation programme.
To explore patients' experiences of activity, participation and quality of life one year after a rehabilitation programme for chronic pain, and to determine the impact of the programme on their current life situation. Qualitative study with emergent design. The 14 informants were patients with chronic pain who had participated in rehabilitation at a pain clinic. Individual semi-structured interviews were analysed with inductive, qualitative content analysis. The core theme "Change is possible" and the themes "A life ruled by pain" (the situation before rehabilitation), "The penny's dropped" (experience during rehabilitation) and "Live a life, not only survive" (the situation at the time of the interviews) emerged from the data. These themes represent a process through which, during and after rehabilitation, the informants integrated earlier disabling symptoms into a functioning lifestyle. Individuals living with disabling chronic pain can create a better life by integrating their illness. A prerequisite is that healthcare professionals empower patients to develop the strength to take responsibility for their daily lives. This process is facilitated by skills to reduce pain and handle life, plus support from significant others.


Documented consent process for implantable cardioverter-defibrillators and implications for end-of-life care in older adults.
Implantable cardioverter defibrillators (ICDs) reduce mortality in selected patients at risk for life-threatening heart arrhythmias, and their use is increasingly common. However, these devices also confer risk for delivery of unexpected painful shocks during the dying process, thus reducing the quality of palliative care at the end of life. This scenario can be avoided by ICD deactivation in appropriate circumstances but patients will remain unaware of this option if not informed about it. It is not known how often end-of-life implications are discussed with patients prior to ICD implantation, when focus is primarily on the short-term potential complications of the device placement procedure itself. We conducted a retrospective chart review to determine how often end-of-life implications were discussed with patients as part of the informed consent process. We evaluated consent forms and related other chart documentation for 91 patients (ranging from age 60 to 89 years) undergoing first-time ICD placement at a mid-western academic medical center from 2006-2008. Only one chart documented any discussion of end-of-life implications, in a case where the issue was raised by a patient who noted that quality of life was their main focus. Consent was provided by a health care surrogate in only four of the 91 cases. In conclusion, patients giving consent for ICD implantation may be uninformed about the device's potential future impact on end-of-life care, the dying process, and the option for device deactivation. Truly informed consent requires that both short- and long-term potential implications be reviewed with patients.


Results of Total Elbow Arthroplasty with Cementless Implantation of an Alumina Ceramic Elbow Prosthesis for Patients with Rheumatoid Arthritis.
We investigated the long-term clinical results of total elbow arthroplasty (TEA) by cementless fixation of alumina ceramic unlinked elbow prostheses (J-alumina ceramic elbows: JACE) for the reconstruction of elbow joints with rheumatoid arthritis (RA). Seventeen elbows in 17 patients (aged 44-72 years, average 54.8) replaced by JACE TEA without bone cement were investigated. The average follow-up period was 10.7 (range, 1.0-19.3) years. Clinical conditions of each elbow before and after surgery were assessed according to the Mayo Elbow Performance Index (MEPI). Radiographic loosening was defined as a progressive radiolucent line of more than 1 mm that was completely circumferential around the intramedullary stem. The average MEPI significantly improved from 46.8 points preoperatively to 66.8 points at final follow-up (p=0.0226). However, aseptic loosening was noted in 10 of 17 elbows (58.8%) and revision surgery was required in 7 (41.2%). Most loosening was observed on the humeral side. With radiographic loosening and revision surgery defined as the end points, the likelihoods of prosthesis survival were 41.2% and 51.8%, respectively, up to 15 years by Kaplan-Meier analysis. The clinical results of JACE implantation without bone cement were disappointing, with high revision and loosening rates of the humeral component.


Diurnal variation in pain reports in temporomandibular disorder patients and control subjects.
To test the hypothesis that temporomandibular disorder (TMD) patients have characteristic diurnal patterns of pain that are associated with diurnal or nocturnal parafunctions. Experience sampling methods were used to obtain information on pain from subjects (n = 84) diagnosed, according to the Research Diagnostic Criteria for TMD, with myofascial pain, myofascial pain and arthralgia, disc displacement, and from non-TMD controls. Variations in pain as reported on the pager questionnaire form were modeled as linear, exponential, and quadratic effects. Between 8.7% and 23.8% of TMD subjects with pain showed significant patterns to their daily pain reports, compared to 4.5% of non-TMD controls. Groups did not differ significantly in the proportions of those with increasing (59.5%) vs. decreasing (40.5%) pain levels. Self-reported clenching during the day and grinding at night were weakly associated with an increasing or decreasing pattern of pain during the day (P < .10). Pain levels during weekends were significantly lower for all groups. Strongly linear or curvilinear patterns of pain were not characteristic of this sample of subjects. More than half the subjects reported slightly increasing pain during the day, but the variability within groups was considerable. Increasing and decreasing patterns of pain were independent of self-reported daytime and nighttime clenching and grinding. Self-reported pain patterns may not be used to reliably infer the times when parafunctional activities occur. The presence of lower pain levels during the weekend probably reflects reduction in psychosocial stressors associated with the work week.


The role of outer-sphere surface acidity in alkene epoxidation catalyzed by calixarene-Ti(IV) complexes.
Cooperativity between Brønsted acidic defect sites on oxide surfaces and Lewis acid catalyst sites consisting of grafted calixarene-Ti(IV) complexes is investigated for controlling epoxidation catalysis. Materials are synthesized that, regardless of the surface or calixarene substituent, demonstrate nearly identical UV-visible ligand-to-metal charge-transfer bands and Ti K-edge X-ray absorption near edge spectral features consistent with site-isolated, coordinatively unsaturated Ti(IV) atoms. Despite similar Ti frontier orbital energies demonstrated by these spectra, replacing a homogeneous triphenylsilanol ligand with a silanol on a SiO2 surface increases cyclohexene epoxidation rates with tert-butyl hydroperoxide 20-fold per Ti site. Supporting calixarene-Ti active sites on fully hydroxylated Al2O3 or TiO2, which possess lower average surface hydroxyl pKa than that of SiO2, reduces catalytic rates 50-fold relative to SiO2. These effects are consistent with SiO2 surfaces balancing two competing factors that control epoxidation rates-equilibrated hydroperoxide binding at Ti, disfavored by stronger surface Brønsted acidity, and rate-limiting oxygen transfer from this intermediate to alkenes, favored by strongly H-bonding intermediates. These observations also imply that Ti-OSi rather than Ti-OCalix bonds are broken upon hydroperoxide binding to Ti in kinetically relevant steps, which is verified by the lack of a calixarene upper-rim substituent effect on epoxidation rate. The pronounced sensitivity of observed epoxidation rates to the support oxide, in the absence of changes to the Ti coordination environment, provides experimental evidence for the importance of outer-sphere H-bonding interactions for the exceptional epoxidation reactivity of titanium silicalite and related catalysts.


Sera from remitting and secondary progressive multiple sclerosis patients disrupt the blood-brain barrier.
Pathological destruction of blood-brain barrier (BBB) has been thought to be the initial key event in the process of developing multiple sclerosis (MS). The purpose of the present study was to clarify the possible molecular mechanisms responsible for the malfunction of BBB by sera from relapse-remitting MS (RRMS) and secondary progressive MS (SPMS) patients. We evaluated the effects of sera from the patients in the relapse phase of RRMS (RRMS-R), stable phase of RRMS (RRMS-S) and SPMS on the expression of tight junction proteins and vascular cell adhesion protein-1 (VCAM-1), and on the transendothelial electrical resistance (TEER) in human brain microvascular endothelial cells (BMECs). Sera from the RRMS-R or SPMS patients decreased the claudin-5 protein expression and the TEER in BMECs. In RRMS-R, this effect was restored after adding an MMP inhibitor, and the MMP-2/9 secretion by BMECs was significantly increased after the application of patients' sera. In SPMS, the immunoglobulin G (IgG) purified from patients' sera also decreased the claudin-5 protein expression and the TEER in BMECs. The sera and purified IgG from all MS patients increased the VCAM-1 protein expression in BMECs. The up-regulation of autocrine MMP-2/9 by BMECs after exposure to sera from RRMS-R patients or the autoantibodies against BMECs from SPMS patients can compromise the BBB. Both RRMS-S and SPMS sera increased the VCAM-1 expression in the BBB, thus indicating that targeting the VCAM-1 in the BBB could represent a possible therapeutic strategy for even the stable phase of MS and SPMS.


A normal platelet count may not be enough: the impact of admission platelet count on mortality and transfusion in severely injured trauma patients.
Platelets play a central role in hemostasis after trauma. However, the platelet count of most trauma patients does not fall below the normal range (100-450 × 10(9)/L), and as a result, admission platelet count has not been adequately investigated as a predictor of outcome. The purpose of this study was to examine the relationship between admission platelet count and outcomes after trauma. A retrospective cohort study of 389 massively transfused trauma patients. Regression methods and the Kruskal-Wallis test were used to test the association between admission platelet count and 24-hour mortality and units of packed red blood cells (PRBCs) transfused. For every 50 × 10(9)/L increase in admission platelet count, the odds of death decreased 17% at 6 hours (p = 0.03; 95% confidence interval [CI], 0.70-0.99) and 14% at 24 hours (p = 0.02; 95% CI, 0.75-0.98). The probability of death at 24 hours decreased with increasing platelet count. For every 50 × 10(9)/L increase in platelet count, patients received 0.7 fewer units of blood within the first 6 hours (p = 0.01; 95% CI, -1.3 to -0.14) and one less unit of blood within the first 24 hours (p = 0.002; 95% CI, -1.6 to -0.36). The mean number of units of PRBCs transfused within the first 6 hours and 24 hours decreased with increasing platelet count. Admission platelet count was inversely correlated with 24-hour mortality and transfusion of PRBCs. A normal platelet count may be insufficient after severe trauma, and as a result, these patients may benefit from a lower platelet transfusion threshold. Future studies of platelet number and function after injury are needed.


High temperature, high power piezoelectric composite transducers.
Piezoelectric composites are a class of functional materials consisting of piezoelectric active materials and non-piezoelectric passive polymers, mechanically attached together to form different connectivities. These composites have several advantages compared to conventional piezoelectric ceramics and polymers, including improved electromechanical properties, mechanical flexibility and the ability to tailor properties by using several different connectivity patterns. These advantages have led to the improvement of overall transducer performance, such as transducer sensitivity and bandwidth, resulting in rapid implementation of piezoelectric composites in medical imaging ultrasounds and other acoustic transducers. Recently, new piezoelectric composite transducers have been developed with optimized composite components that have improved thermal stability and mechanical quality factors, making them promising candidates for high temperature, high power transducer applications, such as therapeutic ultrasound, high power ultrasonic wirebonding, high temperature non-destructive testing, and downhole energy harvesting. This paper will present recent developments of piezoelectric composite technology for high temperature and high power applications. The concerns and limitations of using piezoelectric composites will also be discussed, and the expected future research directions will be outlined.


Increased protein intake and meal frequency reduces abdominal fat during energy balance and energy deficit.
Unrefined, complex carbohydrates and lean protein diets are used to combat obesity, although it's unknown whether more frequent meals may improve this response. The effects of consuming traditional (~15%) versus higher (~35%) protein intakes as three or six meals/day on abdominal fat, postprandial thermogenesis (TEM), and cardiometabolic biomarkers in overweight individuals during 28 days of energy balance (BAL) and deficit (NEG), respectively were compared. Overweight individuals (n = 30) were randomized into three groups: two high-protein groups (35% of energy) consumed as three (HP3) or six (HP6) meals/day and one group consumed three meals/day of a traditional intake (TD3). Following a 5-day baseline control (CON), subjects consumed their respective diets throughout a 56-day intervention consisting of two, 28 day phases: a BAL followed by a NEG phase (75% of energy needs). Total body fat (BF) and abdominal BF (ABF), body weight (BW), TEM, and fasting biomarkers were assessed at the end of CON, BAL, and NEG phases. BW remained stable throughout CON and BAL in all groups, whereas BF (P < 0.001) and ABF (P < 0.01) decreased in HP groups and lean body mass (LBM) and leptin increased in HP6. Following NEG, BW decreased in all groups. BF, ABF, and leptin decreased in HP groups; LBM remained higher (P < 0.05), and TEM was highest in HP6 (P < 0.05). Consuming increased protein (∼35%) more frequently (6×) throughout the day decreases BF and ABF, increases LBM and TEM, and favorably affects adipokines more than current recommendations for macronutrients consumed over three meals/day in overweight individuals during both BAL and NEG.


Smooth muscle contractile plasticity in rat mesenteric small arteries: sensitivity to specific vasoconstrictors, distension and inflammatory cytokines.
Small artery remodeling may involve a shift in the diameter-dependent force generating capacity of smooth muscle cells (SMC). We tested to what extent and under which conditions such contractile plasticity occurs. Rat mesenteric arteries were mounted on isometric myographs. Active diameter-tension relations were determined after application of several stimuli for 16 or 40 h at 40 or 110% of the passive diameter at 100 mm Hg. At 40%, 16-hour incubation with endothelin-1 (ET-1) but not U46619 shifted force capacity towards smaller diameters. Inflammatory cytokines (TNF-α, IL-1β, IFN-γ), TGF-β or serum neither induced such shift nor augmented the effect of ET-1. The ET-1-mediated change was not affected by superoxide dismutase and catalase. Inward matrix remodeling in the presence of ET-1 was slower, occurring after 40 h. Arteries maintained at 110% showed a shift of force capacity to larger diameters, which was prevented by ET-1 but not by U46619. In the active but not the passive state, SMC had altered nuclear lengths after incubation at 40%. These data demonstrate contractile plasticity in small arteries, where chronic strain is an outward drive and specifically ET-1 an inward drive, acting through mechanisms that do not seem to relate to oxidative stress, inflammatory pathways or major reorganization of the SMC.


Long term gluten consumption in adults without celiac disease and risk of coronary heart disease: prospective cohort study.
Objective To examine the association of long term intake of gluten with the development of incident coronary heart disease.Design Prospective cohort study.Setting and participants 64 714 women in the Nurses' Health Study and 45 303 men in the Health Professionals Follow-up Study without a history of coronary heart disease who completed a 131 item semiquantitative food frequency questionnaire in 1986 that was updated every four years through 2010.Exposure Consumption of gluten, estimated from food frequency questionnaires.Main outcome measure Development of coronary heart disease (fatal or non-fatal myocardial infarction).Results During 26 years of follow-up encompassing 2 273 931 person years, 2431 women and 4098 men developed coronary heart disease. Compared with participants in the lowest fifth of gluten intake, who had a coronary heart disease incidence rate of 352 per 100 000 person years, those in the highest fifth had a rate of 277 events per 100 000 person years, leading to an unadjusted rate difference of 75 (95% confidence interval 51 to 98) fewer cases of coronary heart disease per 100 000 person years. After adjustment for known risk factors, participants in the highest fifth of estimated gluten intake had a multivariable hazard ratio for coronary heart disease of 0.95 (95% confidence interval 0.88 to 1.02; P for trend=0.29). After additional adjustment for intake of whole grains (leaving the remaining variance of gluten corresponding to refined grains), the multivariate hazard ratio was 1.00 (0.92 to 1.09; P for trend=0.77). In contrast, after additional adjustment for intake of refined grains (leaving the variance of gluten intake correlating with whole grain intake), estimated gluten consumption was associated with a lower risk of coronary heart disease (multivariate hazard ratio 0.85, 0.77 to 0.93; P for trend=0.002).Conclusion Long term dietary intake of gluten was not associated with risk of coronary heart disease. However, the avoidance of gluten may result in reduced consumption of beneficial whole grains, which may affect cardiovascular risk. The promotion of gluten-free diets among people without celiac disease should not be encouraged.


Single-trials analyses demonstrate that increases in clock speed contribute to the methamphetamine-induced horizontal shifts in peak-interval timing functions.
Drugs that increase dopamine (DA) transmission have been shown to produce an overestimation of time in duration production procedures as exhibited by horizontal leftward shifts of the psychophysical functions. However, the generality of these results has been inconsistent in the literature. The present report evaluates the effects of five doses of methamphetamine (MAP) (0.5-1.5 mg/kg, i.p.) on two duration production procedures, the single duration peak-interval (PI) procedure and the multiduration tri-peak procedure in rats. We replicated and extended prior results by showing a dose-dependent proportional overestimation of time that was equivalent on both procedures (i.e., subjects behaved as though they expected reinforcement to be available earlier in real time). Single-trials analyses demonstrated that the reduction in peak rate that is often observed after MAP administration is due to an increase in the proportion of trials in which responding occurred at very low rates and without temporal control. However, these low-rate trials were not the source of the leftward shift in the temporal estimates. Rather, we found that the leftward shift of the PI functions was due to proportional changes in the placement of temporally controlled high-rate responding, which is consistent with a DA-mediated alteration in clock speed.


Robust recovery of subspace structures by low-rank representation.
In this paper, we address the subspace clustering problem. Given a set of data samples (vectors) approximately drawn from a union of multiple subspaces, our goal is to cluster the samples into their respective subspaces and remove possible outliers as well. To this end, we propose a novel objective function named Low-Rank Representation (LRR), which seeks the lowest rank representation among all the candidates that can represent the data samples as linear combinations of the bases in a given dictionary. It is shown that the convex program associated with LRR solves the subspace clustering problem in the following sense: When the data is clean, we prove that LRR exactly recovers the true subspace structures; when the data are contaminated by outliers, we prove that under certain conditions LRR can exactly recover the row space of the original data and detect the outlier as well; for data corrupted by arbitrary sparse errors, LRR can also approximately recover the row space with theoretical guarantees. Since the subspace membership is provably determined by the row space, these further imply that LRR can perform robust subspace clustering and error correction in an efficient and effective way.


Successful surgical excision of a gigantic cerebral hydatid cyst.
In this study, an extremely rare case of a gigantic cerebral hydatid cyst is presented. A right frontotemporal hydatid cyst was detected by computed tomography and magnetic resonance imaging. This lesion was extirpated successfully with intact contents with the aid of a neuronavigation system. The literature is reviewed and possible postoperative complications are discussed with the published reports.