'It is safe to use if you are healthy': A discursive analysis of men's online accounts of ephedrine use.
Ephedrine use in sport is a common practice among men. Less well understood is men's use of ephedrine as a slimming aid. Arguably fuelled by the 'war on obesity' and the drive for muscularity, the Internet has become awash with claims presenting ephedrine as safe. The use of this psychoactive substance can have acute health implications such as tachycardia, arrhythmias and cardiovascular disease. Given the tension between health risk and ephedrine-induced weight loss, how men justify their use of ephedrine becomes an important question. In particular, we wished to analyse how male users talked to others about ephedrine in discussions linked to an online version of a popular men's magazine. Because we were particularly interested in how men accounted for their ephedrine use, we used discourse analysis to examine their posts. In analysing the data, we noted that a 'community of practice' was constructed online categorising legitimate (and barred) users, emphasising the benefits of ephedrine and downplaying health-defeating side effects. Our analysis has clear implications for engaging men who use ephedrine in health promotion interventions.


A Guide to Reproducibility in Preclinical Research.
Many have raised concerns about the reproducibility of biomedical research. In this Perspective, the authors address this "reproducibility crisis" by distilling discussions around reproducibility into a simple guide to facilitate understanding of the topic.Reproducibility applies both within and across studies. The following questions address reproducibility within studies: "Within a study, if the investigator repeats the data management and analysis, will she get an identical answer?" and "Within a study, if someone else starts with the same raw data, will she draw a similar conclusion?" Contrastingly, the following questions address reproducibility across studies: "If someone else tries to repeat an experiment as exactly as possible, will she draw a similar conclusion?" and "If someone else tries to perform a similar study, will she draw a similar conclusion?"Many elements of reproducibility from clinical trials can be applied to preclinical research (e.g., changing the culture of preclinical research to focus more on transparency and rigor). For investigators, steps toward improving reproducibility include specifying data analysis plans ahead of time to decrease selective reporting; more explicit data management and analysis protocols; and increasingly detailed experimental protocols, which allow others to repeat experiments. Additionally, senior investigators should take greater ownership of the details of their research (e.g., implementing active laboratory management practices, such as random audits of raw data [or at least reduced reliance on data summaries], more hands-on time overseeing experiments, and encouraging a healthy skepticism from all contributors). These actions will support a culture where rigor + transparency = reproducibility.


Visna virus dUTPase is dispensable for neuropathogenicity.
The major part of the dUTPase-encoding region of the visna virus genome was deleted. Intracerebral injection of the mutant virus resulted in a somewhat reduced viral load compared to that resulting from injection of the wild type, especially in the lungs, but the neuropathogenic effects were comparable. The dUTPase gene is dispensable for induction of lesions in the brain.


Neuronal mechanisms of perceptual learning: changes in human brain activity with training in orientation discrimination.
Using 15O-water 3D positron emission tomography, regional cerebral blood flow was measured twice in six human subjects: before and after extensive training in orientation discrimination. In each session subjects performed two orientation discrimination tasks, during which they discriminated the orientation of a grating at either the trained or untrained reference orientation, and a control task, during which they detected a randomly textured pattern. By comparing the discrimination to the detection tasks, we observed a main effect of task bilaterally in the posterior occipital cortex, extending into the left posterior fusiform gyrus and the right inferior occipital gyrus, bilaterally in the intraparietal sulcus, as well as in the cerebellum, thalamus, and brainstem. When we compared the activation pattern before and after the training period, all the changes observed were activity decreases. The nonspecific changes, which were not related to the orientation used during the training, were situated in the cerebellum and bilaterally in the extrastriate visual cortex. The orientation-specific changes, on the other hand, were restricted to the striate and extrastriate visual cortex, more precisely the right calcarine sulcus, the left lingual gyrus, the left middle occipital, and the right inferior occipital gyrus. These findings confirm our hypothesis concerning the existence of learning related changes at early levels of visual processing in human adults and suggest that mechanisms resulting in neuronal activity decreases might be involved in the present kind of learning.


The role of antibody concentration and avidity in antiviral protection.
Neutralizing antibodies are necessary and sufficient for protection against infection with vesicular stomatitis virus (VSV). The in vitro neutralization capacities and in vivo protective capacities of a panel of immunoglobulin G monoclonal antibodies to the glycoprotein of VSV were evaluated. In vitro, neutralizing activity correlated with avidity and with neutralization rate constant, a measure of on-rate. However, in vivo, protection was independent of immunoglobulin subclass, avidity, neutralization rate constant, and in vitro neutralizing activity; above a minimal avidity threshold, protection depended simply on a minimum serum concentration. These two biologically defined thresholds of antibody specificity offer hope for the development of adoptive therapy with neutralizing antibodies.


Flavonoid Extract from Propolis Provides Cardioprotection following Myocardial Infarction by Activating PPAR-γ.
We have previously reported that flavonoid extract from propolis (FP) can improve cardiac function in rats following myocardial infarction (MI). However, the mechanisms responsible for the cardioprotective effects of FP have not been fully elucidated. In the current study, we explored whether FP can reduce inflammatory cytokines and attenuate sympathetic nerve system activity and antiendoplasmic reticulum (ER) stress and whether the cardioprotective effects are related to peroxisome proliferator-activated receptor gamma (PPAR-γ) activation. Sprague Dawley rats were randomly divided into six groups: Sham group received the surgical procedure but no artery was ligated; MI group received ligation of the left anterior descending (LAD) branch of the coronary artery; MI + FP group received FP (12.5 mg/kg/d, intragastrically) seven days prior to LAD ligation; FP group (Sham group + 12.5 mg/kg/d, intragastrically); MI + FP + GW9662 group received FP prior to LAD ligation with the addition of a specific PPAR-γ inhibitor (GW9662), 1 mg/kg/d, orally); and MI + GW9662 group received the PPAR-γ inhibitor and LAD ligation. The results demonstrated that the following inflammatory markers were significantly elevated following MI as compared with expression in sham animals: IL-1β, TNF-α, CRP; markers of sympathetic activation: plasma norepinephrine, epinephrine and GAP43, nerve growth factor, thyroid hormone; and ER stress response markers GRP78 and CHOP. Notably, the above changes were attenuated by FP, and GW9662 was able to alleviate the effect of FP. In conclusion, FP induces a cardioprotective effect following myocardial infarction by activating PPAR-γ, leading to less inflammation, cardiac sympathetic activity, and ER stress.


Value, Access, and Cost of Cancer Care Delivery at Academic Cancer Centers.
Key challenges facing the oncology community today include access to appropriate, high quality, patient-centered cancer care; defining and delivering high-value care; and rising costs. The National Comprehensive Cancer Network convened a Work Group composed of NCCN Member Institution cancer center directors and their delegates to examine the challenges of access, high costs, and defining and demonstrating value at the academic cancer centers. The group identified key challenges and possible solutions to addressing these issues. The findings and recommendations of the Work Group were then presented at the Value, Access, and Cost of Cancer Care Policy Summit in September 2015 and multi-stakeholder roundtable panel discussions explored these findings and recommendations along with additional items.


Determinants of Arbovirus Vertical Transmission in Mosquitoes.
Vertical transmission (VT) and horizontal transmission (HT) of pathogens refer to parental and non-parental chains of host-to-host transmission. Combining HT with VT enlarges considerably the range of ecological conditions in which a pathogen can persist, but the factors governing the relative frequency of each transmission mode are poorly understood for pathogens with mixed-mode transmission. Elucidating these factors is particularly important for understanding the epidemiology of arthropod-borne viruses (arboviruses) of public health significance. Arboviruses are primarily maintained by HT between arthropod vectors and vertebrate hosts in nature, but are occasionally transmitted vertically in the vector population from an infected female to her offspring, which is a proposed maintenance mechanism during adverse conditions for HT. Here, we review over a century of published primary literature on natural and experimental VT, which we previously assembled into large databases, to identify biological factors associated with the efficiency of arbovirus VT in mosquito vectors. Using a robust statistical framework, we highlight a suite of environmental, taxonomic, and physiological predictors of arbovirus VT. These novel insights contribute to refine our understanding of strategies employed by arboviruses to persist in the environment and cause substantial public health concern. They also provide hypotheses on the biological processes underlying the relative VT frequency for pathogens with mixed-mode transmission that can be tested empirically.


The Utility of Next-Generation Sequencing in Gene Discovery for Mutation-Negative Patients with Rett Syndrome.
Rett syndrome (RTT) is a rare, severe disorder of neuronal plasticity that predominantly affects girls. Girls with RTT usually appear asymptomatic in the first 6-18 months of life, but gradually develop severe motor, cognitive, and behavioral abnormalities that persist for life. A predominance of neuronal and synaptic dysfunction, with altered excitatory-inhibitory neuronal synaptic transmission and synaptic plasticity, are overarching features of RTT in children and in mouse models. Over 90% of patients with classical RTT have mutations in the X-linked methyl-CpG-binding (MECP2) gene, while other genes, including cyclin-dependent kinase-like 5 (CDKL5), Forkhead box protein G1 (FOXG1), myocyte-specific enhancer factor 2C (MEF2C), and transcription factor 4 (TCF4), have been associated with phenotypes overlapping with RTT. However, there remain a proportion of patients who carry a clinical diagnosis of RTT, but who are mutation negative. In recent years, next-generation sequencing technologies have revolutionized approaches to genetic studies, making whole-exome and even whole-genome sequencing possible strategies for the detection of rare and de novo mutations, aiding the discovery of novel disease genes. Here, we review the recent progress that is emerging in identifying pathogenic variations, specifically from exome sequencing in RTT patients, and emphasize the need for the use of this technology to identify known and new disease genes in RTT patients.


Influence of protein supplementation during late pregnancy and lactation on the resistance of Santa Ines and Ile de France ewes to Haemonchus contortus.
This experiment aimed to evaluate the effect of periparturient metabolizable protein (MP) nutrition on resistance to Haemonchus contortus in single rearing Ile de France and Santa Ines ewes. The restriction-fed iso-energetic diet was calculated to provide either 0.8 (low MP diet) or 1.3 (high MP diet) times MP, from three weeks before parturition until eight weeks into lactation. The ewes were experimentally infected with 1000 H. contortus infective larvae (L3) three times a week (Mondays, Wednesdays and Fridays), starting five weeks before the predicted date for parturition until a total of 15,000 L3 had been administered. While both breeds showed elevated fecal egg counts (FEC), these values were significantly lower for Santa Ines ewes than Ile de France ewes, but were independent of level of MP feeding. The latter also did not affect lamb weight gain and ewe body weight variation in each breed. Packed cell volume and total plasma protein for Santa Ines in all periods were significantly higher than those for Ile de France ewes (P<0.01) but were not affected by nutrition. In contrast, levels of serum IgG and IgA antibodies against somatic H. contortus infective larvae and adult antigens were similar between breeds but higher in animals that received high MP diets (P<0.05). The reduced body score of ewes at the beginning of the experiment probably influenced their high susceptibility to incoming larvae. Since, unexpectedly, MP scarcity was not achieved in this experiment, our data support the view that Santa Ines ewes are more resistant to H. contortus than Ile de France ewes.


Keeping pace with the data: 2008 update on the Bioinformatics Links Directory.
The Bioinformatics Links Directory, http://bioinformatics.ca/links_directory/, is an online resource for public access to all of the life science research web servers published in this and previous issues of Nucleic Acids Research, together with other useful tools, databases and resources for bioinformatics and molecular biology research. Dependent on community input and development, the Bioinformatics Links Directory exemplifies an open access research tool and resource. The 2008 update includes the 94 web servers featured in the July 2008 Web Server issue of Nucleic Acids Research, bringing the total number of servers listed in the Bioinformatics Links Directory to over 1200 links. A complete list of all links listed in this Nucleic Acids Research 2008 Web Server issue can be accessed online at http://bioinfomatics.ca/links_directory/narweb2008/. The 2008 update of the Bioinformatics Links Directory, which includes the Web Server list and summaries, is also available online at the Nucleic Acids Research website, http://nar.oxfordjournals.org/.


Changing ecologies, shifting behaviours: Behavioural responses of a rainforest primate, the lion-tailed macaque Macaca silenus, to a matrix of anthropogenic habitats in southern India.
With the uncontrolled expansion of anthropogenic modifications of the environment, wildlife species are forced to interact with humans, often leading to conflict situations that have detrimental effects for both wildlife and humans. Such interactions are escalating globally, making it crucial for us to devise strategies for both, the management of conflict and the conservation of these often-threatened species. We studied a case of potentially detrimental human-wildlife interactions between an endemic, habitat-specialist primate, the lion-tailed macaque Macaca silenus and resident human communities that has developed in recent years in the Western Ghats mountains of southern India. Primates provide useful model systems to understand the extent and nature of behavioural changes exhibited by wildlife in response to anthropogenic habitats with varying degrees of human influence. We documented behaviours, including foraging and intra-species social interactions, to examine the decisions made by the macaques as they exploited four human-modified habitats, which, for the purpose of this study, have been qualitatively characterised to include structural features of the habitat, type of food resources available and the presence of humans. Access to human-origin food, either cooked or packaged, acquired directly from homes or garbage pits, in the human-dominated habitat appeared to significantly reduce active foraging and searching for food, allowing them to engage in other behavioural activities, such as resting. Furthermore, patterns of reciprocated affiliation dissipated in certain human-dominated habitats, with individuals seeming to have adopted novel behavioural strategies, leading to altered social dynamics in the troop, possibly in response to provisioning. This study thus highlights the importance of understanding behavioural changes displayed by animals in response to human interactions; such knowledge could be crucial for the planning and implementation of management and conservation strategies for endangered species such as the lion-tailed macaque and possibly other wildlife in the increasingly anthropogenic landscapes of the tropical world.


RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity.
Carpenter syndrome is a pleiotropic disorder with autosomal recessive inheritance, the cardinal features of which include craniosynostosis, polysyndactyly, obesity, and cardiac defects. Using homozygosity mapping, we found linkage to chromosome 6p12.1-q12 and, in 15 independent families, identified five different mutations (four truncating and one missense) in RAB23, which encodes a member of the RAB guanosine triphosphatase (GTPase) family of vesicle transport proteins and acts as a negative regulator of hedgehog (HH) signaling. In 10 patients, the disease was caused by homozygosity for the same nonsense mutation, L145X, that resides on a common haplotype, indicative of a founder effect in patients of northern European descent. Surprisingly, nonsense mutations of Rab23 in open brain mice cause recessive embryonic lethality with neural-tube defects, suggesting a species difference in the requirement for RAB23 during early development. The discovery of RAB23 mutations in patients with Carpenter syndrome implicates HH signaling in cranial-suture biogenesis--an unexpected finding, given that craniosynostosis is not usually associated with mutations of other HH-pathway components--and provides a new molecular target for studies of obesity.


Combining comparative proteomics and molecular genetics uncovers regulators of synaptic and axonal stability and degeneration in vivo.
Degeneration of synaptic and axonal compartments of neurons is an early event contributing to the pathogenesis of many neurodegenerative diseases, but the underlying molecular mechanisms remain unclear. Here, we demonstrate the effectiveness of a novel "top-down" approach for identifying proteins and functional pathways regulating neurodegeneration in distal compartments of neurons. A series of comparative quantitative proteomic screens on synapse-enriched fractions isolated from the mouse brain following injury identified dynamic perturbations occurring within the proteome during both initiation and onset phases of degeneration. In silico analyses highlighted significant clustering of proteins contributing to functional pathways regulating synaptic transmission and neurite development. Molecular markers of degeneration were conserved in injury and disease, with comparable responses observed in synapse-enriched fractions isolated from mouse models of Huntington's disease (HD) and spinocerebellar ataxia type 5. An initial screen targeting thirteen degeneration-associated proteins using mutant Drosophila lines revealed six potential regulators of synaptic and axonal degeneration in vivo. Mutations in CALB2, ROCK2, DNAJC5/CSP, and HIBCH partially delayed injury-induced neurodegeneration. Conversely, mutations in DNAJC6 and ALDHA1 led to spontaneous degeneration of distal axons and synapses. A more detailed genetic analysis of DNAJC5/CSP mutants confirmed that loss of DNAJC5/CSP was neuroprotective, robustly delaying degeneration in axonal and synaptic compartments. Our study has identified conserved molecular responses occurring within synapse-enriched fractions of the mouse brain during the early stages of neurodegeneration, focused on functional networks modulating synaptic transmission and incorporating molecular chaperones, cytoskeletal modifiers, and calcium-binding proteins. We propose that the proteins and functional pathways identified in the current study represent attractive targets for developing therapeutics aimed at modulating synaptic and axonal stability and neurodegeneration in vivo.


The insulin-like growth factor-1 and expression of its binding protein‑3 in chronic hepatitis C and hepatocellular carcinoma.
The role of growth factors produced by the liver, including insulin-like growth factor-1 (IGF-1) and its main binding protein, IGF binding protein-3 (IGFBP-3), in hepatitis C virus (HCV)-associated carcinogenesis has only partially been recognized and there is not much data available on the local expression of IGF-1 and IGFBP-3 in chronic hepatitis C (CH‑C). Therefore, the aim of the present study was to evaluate the IGF‑1 and IGFBP‑3 serum levels and tissue expression in liver biopsies of CH‑C patients (n=37) and hepatocellular carcinoma (HCC) samples (n=61) as related to age- and gender-matched control serum samples (n=15) and healthy liver samples (n=10). Serum concentrations of IGF-1 (S-IGF-1) and IGFBP‑3 (S-IGFBP‑3) were measured by the ELISA method. Tissue expression of proteins was detected using ABC immunocytochemistry and evaluated applying a spatial visualization technique. Concentrations of S-IGF-1 and hepatic expression of IGF-1 (H-IGF-1) proved to be lower in CH-C compared to the controls. No significant differences were detected in the concentration of S-IGFBP-3 between the studied groups but the S-IGF-1/IGFBP-3 ratio in the CH-C group was significantly lower compared to the control. H-IGFBP-3 was higher in CH-C compared to those in the control and HCC. In HCC, lower expression of H-IGF-1 was detected compared to the control and a higher H-IGF-1/IGFBP-3 ratio compared to CH-C. A negative correlation was detected between S-IGF-1 and S-IGF-1/IGFBP-3 ratio, on the one hand, and age, grading and concentration of α-fetoprotein (AFP) on the other, while H-IGFBP-3 was negatively correlated with BMI in the CH‑C group. In patients with CH‑C, the H‑IGF‑1/IGFBP‑3 ratio was higher compared to that of the S‑IGF‑1/IGFBP‑3 ratio. The studies documented a disturbed H‑IGF‑1 and H‑IGFBP‑3 in CH‑C, which may be of significance in carcinogenesis. Examination of serum concentration and tissue expression of the two proteins and, first of all, estimation of the IGF‑1/IGFBP‑3 ratio may provide additional (to the estimation of IGF‑1 and AFP) non-invasive markers in HCV‑related liver injury.


Genome-Wide Association Study of Serum Fructosamine and Glycated Albumin in Adults Without Diagnosed Diabetes: Results From the Atherosclerosis Risk in Communities Study.
Fructosamine and glycated albumin are potentially useful alternatives to hemoglobin A1c (HbA1c) as diabetes biomarkers. The genetic determinants of fructosamine and glycated albumin, however, are unknown. We performed genome-wide association studies of fructosamine and glycated albumin among 2,104 black and 7,647 white participants without diabetes in the Atherosclerosis Risk in Communities (ARIC) Study and replicated findings in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Among whites, rs34459162, a novel missense single nucleotide polymorphism (SNP) in RCN3, was associated with fructosamine (P = 5.3 × 10-9) and rs1260236, a known diabetes-related missense mutation in GCKR, was associated with percent glycated albumin (P = 5.9 × 10-9) and replicated in CARDIA. We also found two novel associations among blacks: an intergenic SNP, rs2438321, associated with fructosamine (P = 6.2 × 10-9), and an intronic variant in PRKCA, rs59443763, associated with percent glycated albumin (P = 4.1 × 10-9), but these results did not replicate. Few established fasting glucose or HbA1c SNPs were also associated with fructosamine or glycated albumin. Overall, we found genetic variants associated with the glycemic information captured by fructosamine and glycated albumin as well as with their nonglycemic component. This highlights the importance of examining the genetics of hyperglycemia biomarkers to understand the information they capture, including potential glucose-independent factors.


A New Method for Studying the Atom: Optical spectra for multiply ionized atoms are produced by means of nuclear-physics techniques.
The new spectroscopy is in its infancy, and many fascinating aspects are yet to be studied. The properties of thin films may be studied by means of the excitation they induce in a given kind of beam. The production of ions with but a single electron offers a means of carefully mapping the nuclear charge distribution without the complications introduced by the normal complement of electrons. The study of high-purity, multiply ionized particles should make for better temperature determinations in hot plasmas. Possibly the data on lifetimes and modes of decay of excited energy levels may assist in the quantitative assignment of element abundances in the stars. One can even attempt to use the glowing beams as sources for absorption spectroscopy. The method seems to permit study of every stage of excitation for every stage of ionization for every element in the periodic table. Practical problems may interfere with so complete a study, but a major extension of our knowledge of atomic structure seems to be at hand.


Lipopolysaccharide-induced up-regulation of activated macrophages in the degenerating taste system.
Unilateral chorda tympani (CT) nerve section and maintenance on a sodium-restricted diet leads to a rapid decrease in neurophysiological taste responses to sodium in the contralateral, intact CT nerve. Up-regulation of immune function with lipopolysaccharide (LPS; 100 microg i.p.) induces a recovery of normal sodium taste responses, suggesting that the sodium-deficient diet is immunosuppressive. In fact, there is a bilateral increase in the number of lingual, activated macrophages in control-fed rats receiving CT nerve section that does not occur in sodium-deficient rats after sectioning. In the current study, we hypothesized that the LPS-induced recovery of normal taste function in sodium-deficient rats is based on an increase in the activated macrophage response to denervation. Rats receiving a unilateral CT nerve section, a sodium-restricted diet, and/or an injection of LPS (100 microg; i.p.) were overdosed with pentobarbital at day 2 postsectioning, and tongues were rapidly dissected and frozen. Cryosections were then immunohistochemically stained to determine the percentage of ED1 staining for activated macrophages or the number of alphabeta or gammadelta T cells. Activated macrophage levels were significantly increased in sodium-restricted rats that received LPS following unilateral CT nerve section, supporting our hypothesis. These novel findings suggest that LPS overcomes the immunosuppression induced by the sodium-restricted diet and also indicate that the immune system plays a role in regulating taste function after neural injury.


Peripersonal space as the space of the bodily self.
Bodily self-consciousness (BSC) refers to experience of one's self as located within an owned body (self-identification) and as occupying a specific location in space (self-location). BSC can be altered through multisensory stimulation, as in the Full Body Illusion (FBI). If participants view a virtual body from a distance being stroked, while receiving synchronous tactile stroking on their physical body, they feel as if the virtual body were their own and they experience, subjectively, to drift toward the virtual body. Here we hypothesized that--while normally the experience of the body in space depends on the integration of multisensory body-related signals within a limited space surrounding the body (i.e. peripersonal space, PPS)--during the FBI the boundaries of PPS would shift toward the virtual body, that is, toward the position of experienced self-location. To test this hypothesis, we used synchronous visuo-tactile stroking to induce the FBI, as contrasted with a control condition of asynchronous stroking. Concurrently, we applied an audio-tactile interaction paradigm to estimate the boundaries of PPS. PPS was measured in front of and behind the participants' body as the distance where tactile information interacted with auditory stimuli looming in space toward the participant's physical body. We found that during synchronous stroking, i.e. when participants experienced the FBI, PPS boundaries extended in the front-space, toward the avatar, and concurrently shrunk in the back-space, as compared to the asynchronous stroking control condition, when FBI was induced. These findings support the view that during the FBI, PPS boundaries translate toward the virtual body, such that the PPS representation shifts from being centered at the location of the physical body to being now centered at the subjectively experienced location of the self.


Human beta-glucuronidase deficiency mucopolysaccharidosis: identification of cross-reactive antigen in cultured fibroblasts of deficient patients by enzyme immunoassay.
An enzyme immunoassay for human beta-glucuronidase was developed to determine the presence or absence of antigenically cross-reactive material (CRM) in patients with beta-glucuronidase deficiency mucopolysaccharidosis. This assay provided a sensitive means of measuring the primary interaction between the enzyme molecule and antibody but required neither pure antigen nor monospecific antiserum, an important consideration, since neither of these was available. Goat antiserum to partially purified human placenta beta-glucuronidase did not recognize differences in normal enzyme from human placenta, liver, fibroblasts, or blood platelets. CRM was identified in fibroblast extracts from all four of the unrelated beta-glucuronidase-deficient patients studied, but titration patterns indicated genetic heterogeneity among these four mutant proteins. Fibroblast enzymes from two obligate heterozygotes were distinguishable immunologically from normal enzyme. The enzyme immunoassay was also used to compare human enzyme with liver enzyme from other mammalian species. CRM was present in liver extracts of all species tested, but the liver enzymes, except for the rabbit, were weakly cross-reactive. We conclude that despite certain limitations, the enzyme immunoassay for human beta-glucuronidase is useful and that all four beta-glucuronidase-deficient patients studied possess CRM.


Psychometric properties of the Iranian version of the Sexual Quality of Life Scale among women.
INTRODUCTION.: Female sexual dysfunction has a known impact on the quality of life. AIM.: The purpose of this study was the translation and validation of an Iranian version of the Sexual Quality of Life questionnaire-Female (SQOL-F) in Iranian women. METHODS.: A population sample of N = 2,675 women aged 17-67 years from Qazvin City of Iran and two clinical population samples (women with sexual dysfunctions N = 295 and women with type 2 diabetes N = 449) participated in the study. A self-constructed demographic questionnaire, the SQOL-F, the Short Form Health Survey (SF-36), and the Female Sexual Function Index (FSFI) were used for data collection. MAIN OUTCOME MEASURES.: Internal consistency and test-retest reliability were examined. Correlations between the SQOL-F, SF-36, and FSFI were assessed with convergent validity. Furthermore, known-groups comparison analysis was conducted to compare differences in SQOL-F scores between healthy women and those with sexual problems and diabetes. Confirmatory factor analysis assessed the factor structure of the SQOL-F. RESULTS.: Cronbach's alpha ranged from 0.84 to 0.98. Significant correlations between the SQOL-F, SF-36, and FSFI scores were found (ranging from r = 0.4 to r = 0.72). The SQOL-F scores were significantly different between women with and without a clinical condition (P < 0.05). A unifactorial model provided the best fit to the data. CONCLUSION.: The questionnaire represents a suitable measure to assess sexuality-related quality of life to sexual function in healthy women, as well as in women suffering from a chronic medical condition. Application of the scale to other clinical samples needs to be further explored.


The dose-dependent effect of copper-chelating agents on the kinetics of peroxidation of low-density lipoprotein (LDL).
Copper-induced peroxidation of lipoproteins involves continuous production of free radicals via a redox cycle of copper. Formation of Cu(I) during Cu(II)-induced peroxidation of LDL was previously demonstrated by accumulation of the colored complexes of Cu(I) in the presence of one of the Cu(I)-specific chelators bathocuproine (BC) or neocuproine (NC). All the studies conducted thus far employed high concentrations of these chelators (chelator/Cu(II) > 10). Under these conditions, at low copper concentrations the chelators prolonged the lag preceding oxidation, whereas at high copper concentrations the chelators shortened the lag. In an attempt to gain understanding of these non-monotonic effects, we have studied systematically the peroxidation of LDL (0.1 microM, 50 microg protein/mL) at varying concentrations of NC or BC over a wide range of concentrations of the chelators and copper. These studies revealed that: (i) At copper concentrations of 5 microM and below, NC prolonged the lag in a monotonic, dose-dependent fashion typical for other complexing agents. However, unlike with other chelators, the maximal rate of oxidation was only slightly reduced (if at all). (ii) At copper concentrations of 15 microM and above, the addition of about 20 microM NC or BC resulted in prolongation of the lag, but this effect became smaller at higher concentrations of the chelators, and at yet higher concentrations the lag became much shorter than that observed in the absence of chelators. Throughout the whole range of NC concentrations, the maximal rate of peroxidation increased monotonically upon increasing the NC concentration. (iii) Unlike in the absence of chelators, the prooxidative effect of copper did not exhibit saturation with respect to copper, up to copper concentrations of 30 microM. Based on these results we conclude that the copper-chelates can partition into the hydrophobic core of LDL particles and induce peroxidation by forming free radicals within the core. This may be significant with respect to the understanding of the possible mechanisms of peroxidation by chelated transition metals in vivo.


Isolation and characterization of human casein kinase I epsilon (CKI), a novel member of the CKI gene family.
The casein kinase I (CKI) gene family is a rapidly enlarging group whose members have been implicated in the control of cytoplasmic and nuclear processes, including DNA replication and repair. We report here the cloning and characterization of a novel isoform of CKI from a human placental cDNA library. The cDNA for this isoform, hCKI epsilon, predicts a basic polypeptide of 416 amino acids and a molecular mass of 47.3 kDa. It encodes a core kinase domain of 285 amino acids and a carboxyl-terminal tail of 123 amino acids. The kinase domain is 53-98% identical to the kinase domains of other CKI family members and is most closely related to the delta isoform. Localization of the hCKI epsilon gene to chromosome 22q12-13 and the hCKI delta gene to chromosome 17q25 confirms that these are distinct genes in the CKI family. Northern blot analysis shows that hCKI epsilon is expressed in multiple human cell lines. Recombinant hCKI epsilon is an active enzyme that phosphorylates known CKI substrates including a CKI-specific peptide substrate and is inhibited by CKI-7, a CKI-specific inhibitor. A budding yeast isoform of CKI, HRR25, has been implicated in DNA repair responses. Expression of hCKI epsilon but not hCKI alpha rescued the slow-growth phenotype of a Saccharomyces cerevisiae strain with a deletion of HRR25. Human CKI epsilon is a novel CKI isoform with properties that overlap those of previously described CKI isoforms.


The Map of Medicine: a review of evidence for its impact on healthcare.
Map of Medicine is an evidence-based online clinical knowledge resource. Procured at significant cost by healthcare providers in the UK, Sweden and Denmark, it is important to establish the beneficial impact that investment has had on healthcare practise and, ultimately, on patient outcomes. The objective of this study is to review the evidence for the impact of the Map of Medicine on clinical practice. A systematic review of peer-reviewed and grey literature was conducted. Nine healthcare databases, Google Scholar and Google were searched for articles containing the terms 'map of medicine'. The search identified 133 articles. Eleven of the articles identified met the inclusion criteria. The main finding of the study is the paucity of evidence available on the impact of the Map of Medicine and the variable quality of that which does exist. There are some encouraging early indications for the Map of Medicine as a tool within service redesign, leading to an increase in appropriate referrals to secondary care, decreased patient waiting times and considerable cost savings. Further research with study designs that can generate high quality evidence for the impact of Map of Medicine is essential in order to support policy decisions.


Amplification of intense light fields by nearly free electrons.
Light can be used to modify and control properties of media, as in the case of electromagnetically induced transparency or, more recently, for the generation of slow light or bright coherent XUV and X-ray radiation. Particularly unusual states of matter can be created by light fields with strengths comparable to the Coulomb field that binds valence electrons in atoms, leading to nearly-free electrons oscillating in the laser field and yet still loosely bound to the core [1,2]. These are known as Kramers-Henneberger states [3], a specific example of laser-dressed states [2]. Here, we demonstrate that these states arise not only in isolated atoms [4,5], but also in rare gases, at and above atmospheric pressure, where they can act as a gain medium during laser filamentation. Using shaped laser pulses, gain in these states is achieved within just a few cycles of the guided field. The corresponding lasing emission is a signature of population inversion in these states and of their stability against ionization. Our work demonstrates that these unusual states of neutral atoms can be exploited to create a general ultrafast gain mechanism during laser filamentation.


The synthesis and analysis of lignin-bound Hibbert ketone structures in technical lignins.
Understanding the structure of technical lignins resulting from acid-catalysed treatment of lignocellulosic biomass is important for their future applications. Here we report an investigation into the fate of lignin under acidic aqueous organosolv conditions. In particular we examine in detail the formation and reactivity of non-native Hibbert ketone structures found in isolated organosolv lignins from both Douglas fir and beech woods. Through the use of model compounds combined with HSQC, HMBC and HSQC-TOCSY NMR experiments we demonstrate that, depending on the lignin source, both S and G lignin-bound Hibbert ketone units can be present. We also show that these units can serve as a source of novel mono-aromatic compounds following an additional lignin depolymerisation reaction.


The effects of taurine supplementation on obesity, blood pressure and lipid profile: A meta-analysis of randomized controlled trials.
Taurine plays a pivotal role in regulating glucose and lipid metabolism, blood pressure homeostasis, and obesity largely due to its cytoprotective, antioxidant, and anti-inflammatory actions. Despite promising data from animal studies in this scenario, the efficacy of taurine supplementation in human studies has been inconsistent. The main objective of this meta-analysis was to appraise the effects of taurine supplementation on liver markers and, secondarily, to explore anthropometric measures as well. Pubmed, SCOPUS, Web of Science, and Google Scholar were searched from inception to April 2020. There were 12 eligible peer-reviewed studies meeting the inclusion criteria. Most studies were conducted in patients with liver or metabolic dysregulation (diabetes, hepatitis, fatty liver, obesity, cystic fibrosis, chronic alcoholism, and cardiac surgery). The taurine dosage varied from 0.5 to 6 g/d for 15 days to 6 months. Pooled effect sizes suggested a significant effect of taurine administration on systolic blood pressure (weighted mean difference (WMD): -4.67 mm Hg; 95%CI, -9.10 to -0.25), diastolic blood pressure (WMD: -2.90 mm Hg; 95%CI, -4.29 to -1.52), total cholesterol (WMD: -10.87 mg/dl; 95%CI, -16.96 to -4.79), and triglycerides (WMD: -13.05 mg/dl; 95%CI, -25.88 to -0.22); however, it had no effect on fasting blood glucose (WMD: 0.06 mg/dl), HDL-C (WMD: 0.90 mg/dl), LDL-C (WMD: -6.17 mg/dl), as well as on body mass index (WMD: -0.46 kg/m2) and body weight (WMD: -0.47 kg) as the anthropometric measures. These findings indicate that, in patients with liver dysregulation, taurine supplementation can lower blood pressure and improve the lipid profile by reducing total cholesterol and triglyceride levels.


Boosting Antitumor Drug Efficacy with Chemically Engineered Multidomain Proteins.
A facile chemical approach integrating supramolecular chemistry, site-selective protein chemistry, and molecular biology is described to engineer synthetic multidomain protein therapeutics that sensitize cancer cells selectively to significantly enhance antitumor efficacy of existing chemotherapeutics. The desired bioactive entities are assembled via supramolecular interactions at the nanoscale into structurally ordered multiprotein complexes comprising a) multiple copies of the chemically modified cyclic peptide hormone somatostatin for selective targeting and internalization into human A549 lung cancer cells expressing SST-2 receptors and b) a new cysteine mutant of the C3bot1 (C3) enzyme from Clostridium botulinum, a Rho protein inhibitor that affects and influences intracellular Rho-mediated processes like endothelial cell migration and blood vessel formation. The multidomain protein complex, SST3-Avi-C3, retargets C3 enzyme into non-small cell lung A549 cancer cells and exhibits exceptional tumor inhibition at a concentration ≈100-fold lower than the clinically approved antibody bevacizumab (Avastin) in vivo. Notably, SST3-Avi-C3 increases tumor sensitivity to a conventional chemotherapeutic (doxorubicin) in vivo. These findings show that the integrated approach holds vast promise to expand the current repertoire of multidomain protein complexes and can pave the way to important new developments in the area of targeted and combination cancer therapy.


Spontaneous symmetry breaking and phase coexistence in two-color networks.
We consider an equilibrium ensemble of large Erdős-Renyi topological random networks with fixed vertex degree and two types of vertices, black and white, prepared randomly with the bond connection probability p. The network energy is a sum of all unicolor triples (either black or white), weighted with chemical potential of triples μ. Minimizing the system energy, we see for some positive μ the formation of two predominantly unicolor clusters, linked by a string of N_{bw} black-white bonds. We have demonstrated that the system exhibits critical behavior manifested in the emergence of a wide plateau on the N_{bw}(μ) curve, which is relevant to a spinodal decomposition in first-order phase transitions. In terms of a string theory, the plateau formation can be interpreted as an entanglement between baby universes in two-dimensional gravity. We conjecture that the observed classical phenomenon can be considered as a toy model for the chiral condensate formation in quantum chromodynamics.


High vulnerability to household food insecurity in a sample of Canadian renter households in government-subsidized housing.
To determine the prevalence and severity of household food insecurity and examine household material circumstances related to food insecurity in a sample of renter households in government-subsidized housing. Cross-sectional data from the 2010 Survey of Household Spending were used to determine the food insecurity status of 455 renter households living in the 10 provinces and receiving a government housing subsidy. Multivariable logistic regressions were conducted to examine the relationship between household characteristics describing material circumstances and food insecurity. One in two households was food insecure. Marginal, moderate and severe food insecurity affected 9.0%, 23.3% and 18.5% of households respectively. Household economic resources, as captured with after-tax income, after-rent income, or total expenditure, had an independent, inverse relationship with food insecurity. Among the other characteristics examined, more adults or children in the household, presence of a member with disability, and receipt of social assistance increased the odds of food insecurity, but receipt of social assistance lost statistical significance when controlling for total expenditure. Presence of a senior in the household was independently associated with lower odds of food insecurity. Our findings suggest that more effective income-based interventions are needed to address food insecurity among low-income households receiving government housing subsidies. A better integration of housing and income-based policies is necessary to support household food security among government-subsidized renter households.


The auxin-resistant diageotropica mutant of tomato responds to gravity via an auxin-mediated pathway.
Hypocotyls of the diageotropica (dgt) mutant of tomato (Lycopersicon esculentum Mill.) do not elongate in response to exogenous auxin, but can respond to gravity. This appears paradoxical in light of the Cholodny-Went hypothesis, which states that shoot gravicurvature results from asymmetric stimulation of elongation by auxin. While light-grown dgt seedlings can achieve correct gravitropic reorientation, the response is slow compared to wild-type seedlings. The sensitivity of dgt seedlings to inhibition of gravicurvature by immersion in auxin or auxin-transport inhibitors is similar to that of wild-type plants, indicating that both an auxin gradient and auxin transport are required for the gravitropic response and that auxin uptake, efflux, and at least one auxin receptor are functional in dgt. Furthermore, dgt gravicurvature is the result of asymmetrically increased elongation as would be expected for an auxin-mediated response. Our results suggest differences between elongation in response to exogenous auxin (absent in dgt) and elongation in response to gravistimulation (present but attenuated in dgt) and confirm the presence of two phases during the gravitropic response, both of which are dependent on functional auxin transport.


Simultaneous Hot Electron and Hole Injection upon Excitation of Gold Surface Plasmon.
We have successfully investigated the simultaneous injection of hot electrons and holes upon excitation of gold localized surface plasmon resonance (LSPR). The studies were performed on all-solid-state plasmonic system composed of titanium dioxide (TiO2)/poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) (PEDOT:PSS) p-n junctions with gold nanoparticles (Au NPs). The study revealed that both charge carriers are transferred within 200 fs to the respective charge acceptors, exhibiting a free carrier transport behavior. We also confirmed that the transfer of charge carriers are accompanied by change in the initial relaxation dynamics of Au NPs.


Beryllium increases the CD14(dim)CD16+ subset in the lung of chronic beryllium disease.
CD14dimCD16+ and CD14brightCD16+ cells, which compose a minor population of monocytes in human peripheral blood mononuclear cells (PBMC), have been implicated in several inflammatory diseases. The aim of this study was to investigate whether this phenotype was present as a subset of lung infiltrative alveolar macrophages (AMs) in the granulomatous lung disease, chronic beryllium disease (CBD). The monocytes subsets was determined from PBMC cells and bronchoalveolar lavage (BAL) cells from CBD, beryllium sensitized Non-smoker (BeS-NS) and healthy subjects (HS) using flow cytometry. The impact of smoking on the AMs cell phenotype was determined by using BAL cells from BeS smokers (BeS-S). In comparison with the other monocyte subpopulations, CD14dimCD16+ cells were at decreased frequency in PBMCs of both BeS-NS and CBD and showed higher HLA-DR expression, compared to HS. The AMs from CBD and BeS-NS demonstrated a CD14dimCD16+phenotype, while CD14brightCD16+ cells were found at increased frequency in AMs of BeS, compared to HS. Fresh AMs from BeS-NS and CBD demonstrated significantly greater CD16, CD40, CD86 and HLA-DR than HS and BeS-S. The expression of CD16 on AMs from both CBD and BeS-NS was downregulated significantly after 10μM BeSO4 stimulation. The phagocytic activity of AMs decreased after 10μM BeSO4 treatment in both BeS-NS and CBD, although was altered or reduced in HS and BeS-S. These results suggest that Be increases the CD14dimCD16+ subsets in the lung of CBD subjects. We speculate that Be-stimulates the compartmentalization of a more mature CD16+ macrophage phenotype and that in turn these macrophages are a source of Th1 cytokines and chemokines that perpetuate the Be immune response in CBD. The protective effect of cigarette smoking in BeS-S may be due to the low expression of co-stimulatory markers on AMs from smokers as well as the decreased phagocytic function.


Modeling damage complexity-dependent non-homologous end-joining repair pathway.
Non-homologous end joining (NHEJ) is the dominant DNA double strand break (DSB) repair pathway and involves several repair proteins such as Ku, DNA-PKcs, and XRCC4. It has been experimentally shown that the choice of NHEJ proteins is determined by the complexity of DSB. In this paper, we built a mathematical model, based on published data, to study how NHEJ depends on the damage complexity. Under an appropriate set of parameters obtained by minimization technique, we can simulate the kinetics of foci track formation in fluorescently tagged mammalian cells, Ku80-EGFP and DNA-PKcs-YFP for simple and complex DSB repair, respectively, in good agreement with the published experimental data, supporting the notion that simple DSB undergo fast repair in a Ku-dependent, DNA-PKcs-independent manner, while complex DSB repair requires additional DNA-PKcs for end processing, resulting in its slow repair, additionally resulting in slower release rate of Ku and the joining rate of complex DNA ends. Based on the numerous experimental descriptions, we investigated several models to describe the kinetics for complex DSB repair. An important prediction of our model is that the rejoining of complex DSBs is through a process of synapsis formation, similar to a second order reaction between ends, rather than first order break filling/joining. The synapsis formation (SF) model allows for diffusion of ends before the synapsis formation, which is precluded in the first order model by the rapid coupling of ends. Therefore, the SF model also predicts the higher number of chromosomal aberrations observed with high linear energy transfer (LET) radiation due to the higher proportion of complex DSBs compared to low LET radiation, and an increased probability of misrejoin following diffusion before the synapsis is formed, while the first order model does not provide a mechanism for the increased effectiveness in chromosomal aberrations observed.


Phase 1 study of combinatorial sorafenib, G-CSF, and plerixafor treatment in relapsed/refractory, FLT3-ITD-mutated acute myelogenous leukemia patients.
Stroma-leukemia interactions mediated by CXCR4, CD44, VLA4, and their respective ligands contribute to therapy resistance in FLT3-ITD-mutated acute myelogenous leukemia (AML). We conducted a phase 1 study with the combination of sorafenib (a FLT3-ITD inhibitor), plerixafor (a SDF-1/CXCR4 inhibitor), and G-CSF (that cleaves SDF-1, CD44, and VLA4). Twenty-eight patients with relapsed/refractory FLT3-ITD-mutated AML were enrolled from December 2010 to December 2013 at three dose levels of sorafenib (400, 600, and 800 mg twice daily) and G-CSF and plerixafor were administered every other day for seven doses starting on day one. Sorafenib 800 mg twice daily was selected for the expansion phase. While no dose-limiting toxicities (DLT) were encountered in the four-week DLT window, hand-foot syndrome and rash were seen beyond the DLT window, which required dose reductions in most patients. The response rate was 36% (complete response (CR) = 4, complete remission with incomplete platelet recovery (CRp) = 4, complete remission with incomplete hematologic recovery (CRi) = 1, and partial response (PR) = 1) for the intention to treat population. Treatment resulted in 58.4 and 47 mean fold mobilization of blasts and CD34 /38- stem/progenitor cells, respectively, to the circulation. Expression of the adhesion molecules CXCR4, CD44, and VLA4 on circulating leukemia cells correlated negatively with the mobilization of CD34+/38-, CD34+/38-/123+ "progenitor" cells (all P ≤ .002). Mass cytometry analysis of sequential samples from two patients demonstrated resistance emerging early on from sub-clones with persistent Akt and/or ERK signaling. In conclusion, the strategy of combined inhibition of FLT3 kinase and stromal adhesive interactions has promising activity in relapsed/refractory, FLT3-ITD-mutated AML, which warrants further evaluation in the front-line setting.


Emergency intracardiac defibrillation for refractory ventricular fibrillation during routine electrophysiologic study.
Ventricular fibrillation refractory to cardiopulmonary resuscitation including multiple transthoracic defibrillations occurred in four patients during 1,215 consecutive ventricular tachycardia induction studies. A technique of emergency intracardiac defibrillation for management of refractory ventricular fibrillation is described. In four patients, stable monomorphic ventricular tachycardia (320 to 570 ms cycle length) was induced during the study and overdrive ventricular pacing resulted in ventricular fibrillation. These patients did not respond to prompt transthoracic defibrillations (5 to 15 attempts/patient) and cardiopulmonary resuscitation, including antiarrhythmic therapy. As a last resort, intracardiac defibrillation was performed with use of a previously inserted standard right ventricular quadripolar catheter as cathode and a posterior skin patch as anode. High energy intracardiac defibrillation pulses (100 to 500 J) delivered from a standard defibrillator successfully terminated each arrhythmia. Intracardiac defibrillation is technically simple and appears effective in terminating refractory ventricular fibrillation in the electrophysiology laboratory. However, further research is necessary to determine the safety and efficacy of this technique, as well as potential applications in other emergency settings.


Renal clearance of the thyrotropin-releasing hormone-like peptide pyroglutamyl-glutamyl-prolineamide in humans.
TRH-like peptides have been identified that differ from TRH (pGlu-His-ProNH2) in the middle amino acid. We have estimated TRH-like immunoreactivity (TRH-LI) in human serum and urine by RIA with TRH-specific antiserum 8880 or with antiserum 4319, which binds most peptides with the structure pGlu-X-ProNH2. TRH was undetectable in serum (< 25 pg/mL), but TRH-LI was detected with antiserum 4319 in serum of 27 normal subjects, 21 control patients, and 12 patients with carcinoid tumors (range 17-45, 5-79, and 18-16,600 pg/mL, respectively). Because serum was kept for at least 2 h at room temperature, which causes degradation of TRH, pGlu-Phe-ProNH2, and pGlu-Tyr-ProNH2, serum TRH-LI is not caused by these peptides. On high-performance liquid chromatography, serum TRH-LI coeluted with pGlu-Glu-ProNH2 (< EEP-NH2), a peptide produced in, among others, the prostate. Urine of normals and control patients also contained TRH-LI (range 1.14-4.97 and 0.24-5.51 ng/mL, respectively), with similar levels in males and females. TRH represented only 2% of urinary TRH-LI, and anion-exchange chromatography and high-performance liquid chromatography revealed that most TRH-LI in urine was < EEP-NH2. In patients with carcinoid tumors, increased urinary TRH-LI levels were noted (range 1.35-962.4 ng/mL). Urinary TRH-LI correlated positively with urinary creatinine, and the urinary clearance rate of TRH-LI was similar to the glomerular filtration rate. In addition, serum TRH-LI was increased in 17 hemodialysis patients (43-373 pg/mL). This suggests that serum < EEP-NH2 is cleared by glomerular filtration with little tubular resorption. The possible role of the prostate as a source of urinary TRH-LI was evaluated in 11 men with prostate cancer, showing a 25% decrease in urinary TRH-LI excretion after prostatectomy (0.19 +/- 0.02 vs. 0.15 +/- 0.01 ng/mumol creatinine, mean +/- SEM). However, TRH-LI was similar in spontaneously voided urine and in urine obtained through a nephrostomy cannula from 16 patients with unilateral urinary tract obstruction (0.15 +/- 0.01 vs. 0.14 +/- 0.01 ng/mumol creatinine). These data indicate that: 1) TRH-LI in human serum represents largely < EEP-NH2, which is cleared by renal excretion; 2) part of urinary < EEP-NH2 is derived from prostatic secretion into the blood and not directly into urine; and 3) urinary < EEP-NH2 can be used as marker for carcinoid tumors.


Proliferation Genes Repressed by TGF-β Are Downstream of Slug/Snail2 in Normal Bronchial Epithelial Progenitors and Are Deregulated in COPD.
Slug/Snail2 belongs to the Epithelial-Mesenchymal Transition (EMT)-inducing transcription factors involved in development and diseases. Slug is expressed in adult stem/progenitor cells of several epithelia, making it unique among these transcription factors. To investigate Slug role in human bronchial epithelium progenitors, we studied primary bronchial basal/progenitor cells in an air-liquid interface culture system that allows regenerating a bronchial epithelium. To identify Slug downstream genes we knocked down Slug in basal/progenitor cells from normal subjects and subjects with COPD, a respiratory disease presenting anomalies in the bronchial epithelium and high levels of TGF-β in the lungs. We show that normal and COPD bronchial basal/progenitors, even when treated with TGF-β, express both epithelial and mesenchymal markers, and that the epithelial marker E-cadherin is not a target of Slug and, moreover, positively correlates with Slug. We reveal that Slug downstream genes responding to both differentiation and TGF-β are different in normal and COPD progenitors, with in particular a set of proliferation-related genes that are among the genes repressed downstream of Slug in normal but not COPD. In COPD progenitors at the onset of differentiation in presence of TGF-β,we show that there is positive correlations between the effect of differentiation and TGF-β on proliferation-related genes and on Slug protein, and that their expression levels are higher than in normal cells. As well, the expression of Smad3 and β-Catenin, two molecules from TGF-βsignaling pathways, are higher in COPD progenitors, and our results indicate that proliferation-related genes and Slug protein are increased by different TGF-β-induced mechanisms.


Bright Stretchable Alternating Current Electroluminescent Displays Based on High Permittivity Composites.
A high permittivity composite is developed to enhance the brightness of stretchable electroluminescent displays. The unique two-step assembly process yields dense layers, in which the voids around the electroluminescent particles are filled with smaller high dielectric particles. A stretchable seven-segment display based on the composite is bright enough to be used under standard indoor lighting conditions.


Architectural and biochemical expressions of mustard gas keratopathy: preclinical indicators and pathogenic mechanisms.
A subset of victims of ocular sulfur mustard (SM) exposure develops an irreversible, idiotypic keratitis with associated secondary pathologies, collectively referred to as mustard gas keratopathy (MGK). MGK involves a progressive corneal degeneration resulting in chronic ocular discomfort and impaired vision for which clinical interventions have typically had poor outcomes. Using a rabbit corneal vapor exposure model, we previously demonstrated a clinical progression with acute and chronic sequelae similar to that observed in human casualties. However, a better understanding of the temporal changes that occur during the biphasic SM injury is crucial to mechanistic understanding and therapeutic development. Here we evaluate the histopathologic, biochemical and ultrastructural expressions of pathogenesis of the chronic SM injury over eight weeks. We confirm that MGK onset exhibits a biphasic trajectory involving corneal surface regeneration over the first two weeks, followed by the rapid development and progressive degeneration of corneal structure. Preclinical markers of corneal dysfunction were identified, including destabilization of the basal corneal epithelium, basement membrane zone abnormalities and stromal deformation. Clinical sequelae of MGK appeared abruptly three weeks after exposure, and included profound anterior edema, recurring corneal erosions, basement membrane disorganization, basal cell necrosis and stromal degeneration. Unlike resolved corneas, MGK corneas exhibited frustrated corneal wound repair, with significantly elevated histopathology scores. Increased lacrimation, disruption of the basement membrane and accumulation of pro-inflammatory mediators in the aqueous humor provide several mechanisms for corneal degeneration. These data suggest that the chronic injury is fundamentally distinct from the acute lesion, involving injury mechanisms that operate on different time scales and in different corneal tissues. Corneal edema appears to be the principal pathology of MGK, in part resulting from persistent necrosis of the basal corneal epithelium and deterioration of the basement membrane. The findings also provide a potential explanation as to why administration of anti-inflammatories transiently delays, but does not prevent, the development of MGK sequelae.


Computational Analysis of the Domain Architecture and Substrate-Gating Mechanism of Prolyl Oligopeptidases from Shewanella woodyi and Identification of Probable Lead Molecules.
Prolyl oligopeptidases (POPs) are serine proteases found in prokaryotes and eukaryotes which hydrolyze the peptide bond containing proline. The current study focuses on the analysis of POP sequences, their distribution and domain architecture in Shewanella woodyi, a Gram-negative, luminous bacterium which causes celiac sprue and similar infections in marine organisms. The POP undergoes huge interdomain movement, which allows possible route for the entry of any substrate. Hence, it offers an opportunity to understand the mechanism of substrate gating by studying the domain architecture and possibility to identify a probable drug target. In the present study, the POP sequence was retrieved from GenBank database and the best homologous templates were identified by PSI-BLAST search. The three-dimensional structures of the closed and open forms of POP from S. woodyi, which are not available in native form, were generated by homology modeling. The ideal lead molecules were screened by computer-aided virtual screening, and the binding potential of the best leads toward the target was studied by molecular docking. The domain architecture of the POP revealed that it has a propeller domain consists of [Formula: see text]-sheets, surrounded by [Formula: see text]-helices and [Formula: see text] hydrolase domain with catalytic triad containing Ser-564, Asp-646 and His-681. The hypothetical models of open and closed POP showed backbone RMSD value of 0.56 and 0.65 Å, respectively. Ramachandran plot of the open and closed POP conformations accounts for 99.4 and 98.7 % residues in the favoured region, respectively. Our study revealed that propeller domain comes as an insert between N-terminal and C-terminal [Formula: see text] hydrolase domain. Molecular docking, drug likeness properties and ADME prediction suggested that KUC-103481N and Pramiracetum can be used as probable lead molecules toward the POP from S. woodyi.


Functional implications of genetic variation in non-coding DNA for disease susceptibility and gene regulation.
The role of host genetic variation in determining susceptibility to complex disease traits is the subject of much research effort, but it often remains unclear whether disease-associated genetic polymorphisms are themselves functionally relevant or acting only as markers within an extended haplotype. Experimental approaches to investigate the functional impact of polymorphisms in non-coding regulatory DNA sequences for gene expression are discussed, including the role of gel-shift assays, DNA footprinting and reporter gene analysis. The limitations of different experimental approaches are presented together with future prospects for in vivo analysis. The strategic application of these functional approaches is discussed and illustrated by analysis of the role of genetic variation in the tumour necrosis factor promoter region in determining susceptibility to severe malaria.


Automatic tuberculosis screening using chest radiographs.
Tuberculosis is a major health threat in many regions of the world. Opportunistic infections in immunocompromised HIV/AIDS patients and multi-drug-resistant bacterial strains have exacerbated the problem, while diagnosing tuberculosis still remains a challenge. When left undiagnosed and thus untreated, mortality rates of patients with tuberculosis are high. Standard diagnostics still rely on methods developed in the last century. They are slow and often unreliable. In an effort to reduce the burden of the disease, this paper presents our automated approach for detecting tuberculosis in conventional posteroanterior chest radiographs. We first extract the lung region using a graph cut segmentation method. For this lung region, we compute a set of texture and shape features, which enable the X-rays to be classified as normal or abnormal using a binary classifier. We measure the performance of our system on two datasets: a set collected by the tuberculosis control program of our local county's health department in the United States, and a set collected by Shenzhen Hospital, China. The proposed computer-aided diagnostic system for TB screening, which is ready for field deployment, achieves a performance that approaches the performance of human experts. We achieve an area under the ROC curve (AUC) of 87% (78.3% accuracy) for the first set, and an AUC of 90% (84% accuracy) for the second set. For the first set, we compare our system performance with the performance of radiologists. When trying not to miss any positive cases, radiologists achieve an accuracy of about 82% on this set, and their false positive rate is about half of our system's rate.


A randomized double-blind placebo-controlled study of lamivudine in the treatment of patients with chronic hepatitis B virus infection.
To evaluate the effect of lamivudine on the loss of serum hepatitis B virus (HBV) DNA, HBeAg/antiHBe seroconversion and ALT levels in chronic hepatitis B patients and its safety profile and tolerance compared with placebo. Four hundred and twenty-nine patients with chronic HBV infection as defined by positive HBsAg, HBeAg and HBV DNA were enrolled and randomized into lamivudine and placebo groups. Three hundred and twenty-two patients received lamivudine 100 mg daily and 107 patients received placebo treatment for 12 weeks. Then, all patients were offered a further 9-month open label lamivudine treatment. The efficacy and safety were evaluated with clinical, biochemical, hematological and virological parameters. During the 12-week treatment period, 92.2% of lamivudine treated patients became HBV DNA negative (below 1.6 pg/ml) compared with only 14.1% of those receiving placebo (P < 0.01). At the end of 12 week, the sustained negative rate for HBV DNA in the lamivudine treated group was 78.5% compared with the placebo group (11.1%; P < 0.01). There was a trend to a high proportion of patients treated with lamivudine to lose HBeAg (8.1%) and develop antiHBe (10.2%) than treated with placebo (5.3% and 6.4% respectively), but this difference was not statistically significant. Patients with elevated ALT levels at baseline became normal in 60. 3% of the lamivudine treated group compared with the placebo group where only 27.5% were normal (P < 0.01). Lamivudine was well tolerated in a dose of (100 mg daily) and the overall incidence of adverse events was similar to that of the placebo. Lamivudine (100 mg daily) is very effective in the inhibition of HBV replication, indicated by the rapid loss of serum HBV DNA, and often accompanied by a decrease of serum ALT levels. Lamivudine is well tolerated without severe adverse events during treatment.


A randomised controlled study of standard versus accelerated deflation of the Terumo radial band haemostasis device after transradial diagnostic cardiac catheterisation.
Radial access is the preferential access route in patients undergoing diagnostic coronary angiography. We hypothesised that we could reduce hospital stay and improve patient comfort by accelerated deflation of the radial compression device (Terumo radial band). The aim of this study was to compare accelerated pressure reduction with a standard Terumo radial band protocol with regard to local bleeding complications and reported pain scores after cardiac catheterisation. We performed a single centre prospective randomised trial to compare accelerated care to standard care for patients undergoing diagnostic catheterisation through radial access. Patients in the accelerated care group started deflation after 1 hour, with a 2 ml/10-minute interval. Patients in the standard care group started after 2 hours with additional steps of deflation at 3 and 4 hours. Of the 173 analysed patients 86 received accelerated care and 87 patients standard care. A total of 19 patients had pulsatile bleeding, which occurred similarly in the two groups (standard care 11 vs. accelerated care 8, P=0.47). The time to Terumo radial band removal was on average 129 minutes shorter for accelerated care patients compared to standard care ( P<0.01). At 1 hour after Terumo radial band placement, accelerated care patients more often reported pain scores of 0 than standard care patients (89% vs. 74%, P=0.02). There was no increase in local bleedings in the accelerated pressure reduction of the Terumo radial band after diagnostic cardiac catheterisation, increasing patient comfort and reducing hospital stay. These findings will further facilitate the widespread implementation of radial access.


The Ebola virus VP40 matrix layer undergoes endosomal disassembly essential for membrane fusion.
Ebola viruses (EBOVs) assemble into filamentous virions, whose shape and stability are determined by the matrix viral protein 40 (VP40). Virus entry into host cells occurs via membrane fusion in late endosomes; however, the mechanism of how the remarkably long virions undergo uncoating, including virion disassembly and nucleocapsid release into the cytosol, remains unknown. Here, we investigate the structural architecture of EBOVs entering host cells and discover that the VP40 matrix disassembles prior to membrane fusion. We reveal that VP40 disassembly is caused by the weakening of VP40-lipid interactions driven by low endosomal pH that equilibrates passively across the viral envelope without a dedicated ion channel. We further show that viral membrane fusion depends on VP40 matrix integrity, and its disassembly reduces the energy barrier for fusion stalk formation. Thus, pH-driven structural remodeling of the VP40 matrix acts as a molecular switch coupling viral matrix uncoating to membrane fusion during EBOV entry.


Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines.
Glyphosate is a broad-spectrum herbicide that is used worldwide. It represents a potential harm to surface water, and when commercially mixed with surfactants, its uptake is greatly magnified. The most well-known glyphosate-based product is Roundup. This herbicide is potentially an endocrine disruptor and many studies have shown the cytotoxicity potential of glyphosate-based herbicides. In breast cancer (BC) cell lines it has been demonstrated that glyphosate can induce cellular proliferation via estrogen receptors. Therefore, we aimed to identify gene expression changes in ER+ and ER- BC cell lines treated with Roundup and AMPA, to address changes in canonical pathways that would be related or not with the ER pathway, which we believe could interfere with cell proliferation. Using the Human Transcriptome Arrays 2.0, we identified gene expression changes in MCF-7 and MDA-MB-468 exposed to low concentrations and short exposure time to Roundup Original and AMPA. The results showed that at low concentration (0.05% Roundup) and short exposure (48h), both cell lines suffered deregulation of 11 canonical pathways, the most important being cell cycle and DNA damage repair pathways. Enrichment analysis showed similar results, except that MDA-MB-468 altered mainly metabolic processes. In contrast, 48h 10mM AMPA showed fewer differentially expressed genes, but also mainly related with metabolic processes. Our findings suggest that Roundup affects survival due to cell cycle deregulation and metabolism changes that may alter mitochondrial oxygen consumption, increase ROS levels, induce hypoxia, damage DNA repair, cause mutation accumulation and ultimately cell death. To our knowledge, this is the first study to analyze the effects of Roundup and AMPA on gene expression in triple negative BC cells. Therefore, we conclude that both compounds can cause cellular damage at low doses in a relatively short period of time in these two models, mainly affecting cell cycle and DNA repair.


Induced pluripotent stem cells model personalized variations in liver disease resulting from α1-antitrypsin deficiency.
In the classical form of α1-antitrypsin deficiency (ATD), aberrant intracellular accumulation of misfolded mutant α1-antitrypsin Z (ATZ) in hepatocytes causes hepatic damage by a gain-of-function, "proteotoxic" mechanism. Whereas some ATD patients develop severe liver disease (SLD) that necessitates liver transplantation, others with the same genetic defect completely escape this clinical phenotype. We investigated whether induced pluripotent stem cells (iPSCs) from ATD individuals with or without SLD could model these personalized variations in hepatic disease phenotypes. Patient-specific iPSCs were generated from ATD patients and a control and differentiated into hepatocyte-like cells (iHeps) having many characteristics of hepatocytes. Pulse-chase and endoglycosidase H analysis demonstrate that the iHeps recapitulate the abnormal accumulation and processing of the ATZ molecule, compared to the wild-type AT molecule. Measurements of the fate of intracellular ATZ show a marked delay in the rate of ATZ degradation in iHeps from SLD patients, compared to those from no liver disease patients. Transmission electron microscopy showed dilated rough endoplasmic reticulum in iHeps from all individuals with ATD, not in controls, but globular inclusions that are partially covered with ribosomes were observed only in iHeps from individuals with SLD. iHeps model the individual disease phenotypes of ATD patients with more rapid degradation of misfolded ATZ and lack of globular inclusions in cells from patients who have escaped liver disease. The results support the concept that "proteostasis" mechanisms, such as intracellular degradation pathways, play a role in observed variations in clinical phenotype and show that iPSCs can potentially be used to facilitate predictions of disease susceptibility for more precise and timely application of therapeutic strategies.


Manual tapping enhances visual short-term memory performance where visual and motor coordinates correspond.
Visuo-manual interaction in visual short-term memory (VSTM) has been investigated little, despite its importance in everyday tasks requiring the coordination of visual perception and manual action. This study examines the influence of a manual action performed during stimulus learning on a subsequent VSTM test for object appearance. The memory display comprised a sequence of briefly presented 1/f noise discs (i.e., possessing spectral properties akin to natural images), wherein each new stimulus was presented at a unique screen location. Participants either did (or did not) perform a concurrent manual action (spatial tapping) task requiring that a hand-held stylus be moved to a position on a touch tablet that corresponded (or did not correspond) to the screen position of each new stimulus as it appeared. At test, a single stimulus was presented, either at one of the original screen positions, or at a new position. Two factors were examined: the execution (or otherwise) of spatial tapping at a corresponding or non-corresponding position, and the presentation of test stimuli either at their original spatial positions, or at new positions. We find that spatial tapping at corresponding positions elevates VSTM performance by more than 15%, but this occurs only when stimulus positions are matched from memory to test display. Our findings suggest that multimodal attentional focus during stimulus encoding (incorporating visual, spatial, and manual components) leads to stronger, more robust memory representations. We posit several possible explanations for this effect.


Silica desiccant packets for storage and transport of Streptococcus pneumoniae and other clinically relevant species.
Bacterial isolates are often transported between laboratories for research and diagnostic purposes. Silica desiccant packets (SDPs), which are inexpensive and do not require freezing, were evaluated for storage and recovery of bacterial isolates. Conditions such as inoculum size, swab type and temperature of storage were investigated using ten Streptococcus pneumoniae isolates. The optimized protocol was then tested using 49 additional S. pneumoniae isolates representing 40 serogroups. Overall, S. pneumoniae growth was considered satisfactory (>100 colony forming units) for 98/109 (89.9%) and 20/20 (100%) swabs after 14 days at room temperature or 28 days at 4° C, respectively. Storage in SDPs did not impact on the ability of S. pneumoniae isolates to be subsequently serotyped. When the survival of nine other clinically relevant bacterial species was tested, seven were viable after 28 days at room temperature, the exceptions being Neisseria gonorrhoeae and Haemophilus influenzae. SDPs are suitable for transport and short-term storage of bacterial species including S. pneumoniae.


A tandem array of CBF/DREB1 genes is located in a major freezing tolerance QTL region on Medicago truncatula chromosome 6.
Freezing provokes severe yield losses to different fall-sown annual legumes. Understanding the molecular bases of freezing tolerance is of great interest for breeding programs. Medicago truncatula Gaertn. is an annual temperate forage legume that has been chosen as a model species for agronomically and economically important legume crops. The present study aimed to identify positional candidate genes for a major freezing tolerance quantitative trait locus that was previously mapped to M. truncatula chromosome 6 (Mt-FTQTL6) using the LR3 population derived from a cross between the freezing-tolerant accession F83005-5 and the freezing-sensitive accession DZA045-5. The confidence interval of Mt-FTQTL6 was narrowed down to the region comprised between markers MTIC153 and NT6054 using recombinant F7 and F8 lines. A bacterial-artificial chromosome (BAC) clone contig map was constructed in an attempt to close the residual assembly gap existing therein. Twenty positional candidate genes including twelve C-repeat binding factor (CBF)/dehydration-responsive element binding factor 1 (DREB1) genes were identified from BAC-derived sequences and whole-genome shotgun sequences (WGS). CBF/DREB1 genes are organized in a tandem array within an approximately 296-Kb region. Eleven CBF/DREB1 genes were isolated and sequenced from F83005-5 and DZA045-5 which revealed high polymorphism among these accessions. Unique features characterizing CBF/DREB1 genes from M. truncatula, such as alternative splicing and large tandem duplication, are elucidated for the first time. Overall, twenty genes were identified as potential candidates to explain Mt-FTQTL6 effect. Their future functional characterization will uncover the gene(s) involved in freezing tolerance difference observed between F83005-5 and DZA045-5. Knowledge transfer for breeding improvement of crop legumes is expected. Furthermore, CBF/DREB1 related data will certainly have a large impact on research studies targeting this group of transcriptional activators in M. truncatula and other legume species.


Life or death decisions in the corpus luteum.
The corpus luteum (CL) is an ephemeral endocrine organ. During its lifespan, it undergoes a period of extremely rapid growth that involves hypertrophy, proliferation and differentiation of the steroidogenic cells, as well as extensive angiogenesis. The growth phase is followed by a period in which remodelling of the tissue ceases, but it engages in unparalleled production of steroids, resulting in extraordinarily high metabolic activity within the tissue. It is during this stage that a critical juncture occurs. In the non-fertile cycle, uterine release of prostaglandin (PG)F(2α) initiates a cascade of events that result in rapid loss of steroidogenesis and destruction of the luteal tissue. Alternatively, if a viable embryo is present, signals are produced that result in rescue of the CL. This review article summarizes the major concepts related to the fate of the CL, with particular focus on recent insights into the mechanisms associated with the ability of PGF(2α) to bring about complete luteolysis. It has become clear that the achievement of luteolysis depends on repeated exposure to PGF(2α) and involves coordinated actions of heterogeneous cell types within the CL. Together, these components of the process bring about not only the loss in progesterone production, but also the rapid demise of the structure itself.


Cytotoxicity of Cu(II) and Zn(II) 2,2'-bipyridyl complexes: dependence of IC50 on recovery time.
We measure the cytotoxicity of three metal complexes containing the 2,2'-bypyridine ligand, Cu(bpy)(NCS)(2), 1, [Cu(bpy)(2)(H(2)O)](PF(6))(2), 2, and Zn(bpy)(2)(NCS)(2), 3, toward neuroblastoma cells (SK-N-SH) and ovarian cancer cells (OVCAR-3) using two different cell assays. The cells were exposed to various concentrations of the compounds for 1 h and the percent inhibition of cell growth, I, measured for various times after exposure, i.e., as a function of the recovery time t. After developing the theory showing the relationship between I and t, the cytotoxicity data were analyzed to reveal that the two copper complexes, 1 and 2, cause the cells to divide at a slower rate than the controls during the recovery period, but the zinc complex, 3, had little or no effect on cell division during the recovery period. The usual metric for reporting cytotoxicity is IC(50), which is the concentration of agent required to inhibit cell growth to 50% of the control population. However, since IC(50) can depend on the recovery time, t, as is the case for 1 and 2, reporting IC(50) for a single recovery time can hide important information about the long-time effects of a cytotoxic agent on the health of the cell population. Mechanistic studies with the compounds revealed that the copper complexes, 1 and 2, cleave closed circular pBR322 DNA in the presence of ascorbate, while the zinc complex, 3, does not facilitate DNA cleavage under the same conditions. This difference in DNA cleavage activity may be related to the fact that Cu(II) is redox active and can readily change its oxidation state, while Zn(II) is redox inert and cannot participate in a redox cycle with ascorbate to break DNA.


Use of a fan during sleep and the risk of sudden infant death syndrome.
To examine the relation between room ventilation during sleep and risk of sudden infant death syndrome (SIDS). Population-based case-control study. Eleven California counties. Mothers of 185 infants with a confirmed SIDS diagnosis and 312 randomly selected infants matched on county of residence, maternal race/ethnicity, and age. Intervention Fan use and open window during sleep. Main Outcome Measure Risk of SIDS. Fan use during sleep was associated with a 72% reduction in SIDS risk (adjusted odds ratio [AOR], 0.28; 95% confidence interval [CI], 0.10-0.77). The reduction in SIDS risk seemed more pronounced in adverse sleep environments. For example, fan use in warmer room temperatures was associated with a greater reduction in SIDS risk (AOR, 0.06; 95% CI, 0.01-0.52) compared with cooler room temperatures (0.77; 0.22-2.73). Similarly, the reduction associated with fan use was greater in infants placed in the prone or side sleep position (AOR, 0.14; 95% CI, 0.03-0.55) vs supine (0.84; 0.21-3.39). Fan use was associated with a greater reduction in SIDS risk in infants who shared a bed with an individual other than their parents (AOR, 0.15; 95% CI, 0.01-1.85) vs with a parent (0.40; 0.03-4.68). Finally, fan use was associated with reduced SIDS risk in infants not using pacifiers (AOR, 0.22; 95% CI, 0.07-0.69) but not in pacifier users (1.99; 0.16-24.4). Some differences in the effect of fan use on SIDS risk did not reach statistical significance. Fan use may be an effective intervention for further decreasing SIDS risk in infants in adverse sleep environments.


An Endovascular Approach to the Entrapped Central Venous Catheter After Cardiac Surgery.
Entrapment of central venous catheters (CVC) at the superior vena cava (SVC) cardiopulmonary bypass cannulation site by closing purse-string sutures is a rare complication of cardiac surgery. Historically, resternotomy has been required for suture release. An endovascular catheter release approach was developed. Four cases of CVC tethering against the SVC wall and associated resistance to removal, suggestive of entrapment, were encountered. In each case, catheter removal was achieved using a reverse catheter fluoroscopically guided over the suture fixation point between catheter and SVC wall, followed by the placement of a guidewire through the catheter. The guidewire was snared and externalized to create a through-and-through access with the apex of the loop around the suture. A snare placed from the femoral venous access provided concurrent downward traction on the distal CVC during suture release maneuvers. In the initial attempt, gentle traction freed the CVC, which fractured and was removed in two sections. In the subsequent three cases, traction alone did not release the CVC. Therefore, a cutting balloon was introduced over the guidewire and inflated. Gentle back-and-forth motion of the cutting balloon atherotomes successfully incised the suture in all three attempts. No significant postprocedural complications were encountered. During all cases, a cardiovascular surgeon was present in the interventional suite and prepared for emergent resternotomy, if necessary. An endovascular algorithm to the "entrapped CVC" is proposed, which likely reduces risks posed by resternotomy to cardiac surgery patients in the post-operative period.


SAPHO: syndrome or concept? Imaging findings.
The SAPHO syndrome was a term coined to include a variety of musculoskeletal disorders associated with skin conditions, mainly palmoplantar pustulosis and acne conglobata. It is more correctly a spectrum which includes the following: skin lesions, osteoarticular manifestations of synovitis hyperostosis and osteitis affecting particular target sites, and.a clinical course marked by relapses and remissions. The major sites of involvement are the anterior chest wall, the spine, long bones, flat bones, and large and small joints. The distribution and severity of involvement varies from the adult to the pediatric form of chronic recurrent multifocal osteomyelitis (CRMO). The diagnosis of SAPHO syndrome is not difficult when the typical osteoarticular lesions are located in characteristic target sites. The diagnosis is more difficult if atypical sites are involved and there is no skin disease.


Oxygen-limited thermal tolerance is seen in a plastron-breathing insect and can be induced in a bimodal gas exchanger.
Thermal tolerance has been hypothesized to result from a mismatch between oxygen supply and demand. However, the generality of this hypothesis has been challenged by studies on various animal groups, including air-breathing adult insects. Recently, comparisons across taxa have suggested that differences in gas exchange mechanisms could reconcile the discrepancies found in previous studies. Here, we test this suggestion by comparing the behaviour of related insect taxa with different gas exchange mechanisms, with and without access to air. We demonstrate oxygen-limited thermal tolerance in air-breathing adults of the plastron-exchanging water bug Aphelocheirus aestivalis. Ilyocoris cimicoides, a related, bimodal gas exchanger, did not exhibit such oxygen-limited thermal tolerance and relied increasingly on aerial gas exchange with warming. Intriguingly, however, when denied access to air, oxygen-limited thermal tolerance could also be induced in this species. Patterns in oxygen-limited thermal tolerance were found to be consistent across life-history stages in these insects, with nymphs employing the same gas exchange mechanisms as adults. These results advance our understanding of oxygen limitation at high temperatures; differences in the degree of respiratory control appear to modulate the importance of oxygen in setting tolerance limits.


Immediate post-exposure effects of high-peak-power microwave pulses on operant behavior of Wistar rats.
Behavioral effects of high-peak-power microwave pulses on Wistar rats were studied by operant schedules. Each of twelve rats that had been trained to press a lever to receive food pellets was assigned randomly in groups of four to three different schedules of reinforcement: fixed-ratio (FR), variable-interval (VI), and differential-reinforcement-of-low-rates (DRL). After achieving a steady baseline performance, each animal was exposed for 10 min to 1.25-GHz microwave radiation at 1-MW peak-power (10-microseconds pulse width). Each pulse produced a peak whole-body SA and SAR of 2.1 J/kg and 0.21 MW/kg. Total doses (SAs) were set to 0.50, 1.5, 4.5, and 14 kJ/kg by adjusting the pulse-repetition rate. The corresponding time-averaged whole-body SARs were 0.84, 2.5, 7.6, and 23 W/kg. A microwave-transparent animal holder was used to keep the animal's body axis parallel to the E-field. Exposures at the highest dose caused an average colonic temperature rise of 2.5 degrees C and these animals failed to respond at all for about 13 minutes after the exposure. Their colonic temperatures had decreased to 1.1 degrees C, or less, above their pre-exposure (normal) temperature level when they began to respond. The FR and VI animals failed to reach their baseline levels of performance thereafter, while those on the DRL schedule displayed variable effects. No behavioral effects were found at the lower dose levels. It is concluded that the behavioral perturbations produced by pulsed microwave irradiation were thermal in nature.


A microfluidic device for continuous, real time blood plasma separation.
A microfluidic device for continuous, real time blood plasma separation is introduced. The principle of the blood plasma separation from blood cells is supported by the Zweifach-Fung effect and was experimentally demonstrated using simple microchannels. The blood plasma separation device is composed of a blood inlet, a bifurcating region which leads to a purified plasma outlet, and a concentrated blood cell outlet. It was designed to separate blood plasma from an initial blood sample of up to 45% inlet hematocrit (volume percentage of cells). The microfluidic network was designed using an analogous electrical circuit, as well as analytical and numerical studies. The functionality of this device was demonstrated using defibrinated sheep blood. During 30 minutes of continuous blood infusion through the device, all the erythrocytes (red blood cells) traveled through the device toward the concentrated blood outlet while only the plasma was separated at the bifurcating regions and flowed towards the plasma outlet. The device has been operated continuously without any clogging or hemolysis of cells. The experimentally determined plasma selectivity with respect to blood hematocrit level was almost 100% regardless of the inlet hematocrit. The total plasma separation volume percent varied from 15% to 25% with increasing inlet hematocrit. Due to the device's simple structure and control mechanism, this microdevice is expected to be used for highly efficient continuous, real time cell-free blood plasma separation from blood samples for use in lab on a chip applications.


A comparison of a prototype PCR assay and hybrid capture 2 for detection of carcinogenic human papillomavirus DNA in women with equivocal or mildly abnormal papanicolaou smears.
We evaluated Hybrid Capture 2 (HC2) and polymerase chain reaction (PCR) results for paired specimens collected at 19,187 visits from 5,026 of 5,060 women participating in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS). We examined the test agreement between HC2 and PCR detection for any of 13 carcinogenic human papillomavirus types targeted by HC2 and compared clinical performance of the 2 tests for detecting concurrent and follow-up cervical intraepithelial neoplasia (CIN) 3 or cancer. The k value for the 2 assays was 0.65 (95% confidence interval, 0.64-0.66), with 82.7% crude agreement. HC2 was more sensitive (93.6% vs 89.3%; P < .0005) but less specific (41.2% vs 48.5%; P < .0005) than PCR for detecting 2-year cumulative CIN 3 or cancer (n = 503). The presence of multiple types as detected by PCR and/or cytologic abnormality increased the likelihood of an HC2+ result. Increased sensitivity of HC2 compared with PCR was surprising, given the theoretical advantages of PCR-based methods for analytic sensitivity. Smaller amounts of material used in PCR could have limited its sensitivity, but our results demonstrate the importance of optimization and standardization of PCR-based assays for clinical applications.


Dynamical resonances in chemical reactions.
The transition state is a key concept in the field of chemistry and is important in the study of chemical kinetics and reaction dynamics. Chemical reactions in the gas phase are essentially molecular scattering processes, which are quantum mechanical in nature. Thus probing and understanding detailed quantum structure in the transition state region of chemical reactions, such as reactive resonances, is a central topic in this field. In this article, we focus on recent progress in the study of resonances in elementary bimolecular reactions using state-of-the-art transition state spectroscopy methods: high-resolution photoelectron spectroscopy and quantum state specific backward scattering spectroscopy. The experimental results are compared with high-level quantum dynamics calculations based on highly accurate potential energy surfaces. The dynamics of reactive resonances are also interpreted based on scattering wavefunctions obtained by time-dependent wavepacket calculations. Here, we review many systems that illustrate how reactive resonances can strongly influence the dynamics of elementary chemical reactions.


Efficacy of the enamel matrix derivative in direct pulp capping procedures: a systematic review.
The aim was to review the efficacy of the enamel matrix derivative (EMD) in direct pulp capping (DPC) procedures. Databases were explored using the following keywords: 'dental', 'dentine', 'enamel matrix derivative', 'pulp capping' and 'treatment'. The inclusion criteria were: (i) original studies; (ii) human and animal studies; (iii) reference list of potentially relevant original and review articles; (iv) intervention: effect of EMD on pulp-capping procedures; and (v) articles published only in English. Eight studies (four human and four animal) were included. Among the human studies, two studies reported that EMD is a more efficient DPC procedure compared with calcium hydroxide (Ca(OH)2 ). One study reported Ca(OH)2 to be more efficient for DPC than EMD. One study reported no difference in the efficacies between EMD and Ca(OH)2 for DPC. All animal studies reported EMD to be more effective in reparative dentine formation in comparison with Ca(OH)2 . EMD can provide favourable results in DPC procedures.