Effects of proteins from culture medium on surface property of silanes- functionalized magnetic nanoparticles.
Monodisperse magnetic nanoparticles (MNPs) were synthesized by thermal decomposition of iron-oleate and functionalized with silanes bearing various functional groups such as amino group (NH2), short-chain poly(ethylene glycol) (PEG), and carboxylic group (COOH). Then, silanes-functionalized magnetic nanoparticles (silanes-MNPs) were incubated in cell culture medium plus fetal calf serum to investigate the effects of proteins from culture medium on surface property of MNPs. Zeta potential measurements showed that although surface charges of silanes-MNPs were different, they exhibited negative charges at neutral pH and approximate isoelectric points after they were incubated in cell culture medium. The reason was that silanes-MNPs could easily adsorb proteins from culture medium via non-covalent binding, resulting in the formation of protein-silanes-MNPs conjugates. Moreover, silanes-MNPs with various functional groups had different adsorption capacity to proteins, as confirmed by Coomassie blue fast staining method. The in vitro cell experiments showed that protein-silanes-MNPs had higher cellular uptake by cancer cells than silanes-MNPs.


Moxifloxacin five-day therapy versus placebo in acute bacterial rhinosinusitis.
To evaluate the efficacy and safety of moxifloxacin in the treatment of acute bacterial rhinosinusitis (ABRS). Prospective, multicenter, randomized, double-blind, phase III trial. Patients with ABRS defined by clinical, radiologic, and bacteriologic criteria were recruited to the study. Study treatments were 400 mg of oral moxifloxacin or a matching placebo daily for 5 days. The primary end point was clinical response at test-of-cure, 1 to 3 days after the end of therapy in the modified intent-to-treat (mITT) population (patients with positive culture for one of five prespecified pathogens). Secondary efficacy variables included patient-reported symptom improvement measured using the Sino-Nasal Outcome Test-16 (SNOT-16), and concomitant medication use. The mITT population consisted of 118 patients (moxifloxacin, n = 73; placebo, n = 45). Clinical success rates were numerically higher for moxifloxacin (78.1%, 57/73) versus placebo (66.7%, 30/45); (P = .189). Significantly greater mean reductions in SNOT-16 scores occurred in moxifloxacin- versus placebo-treated patients (-17.54 vs. -12.83; P = .032). Overall concomitant medication use was lower in moxifloxacin versus placebo patients (38.4%, 28/73 vs. 55.6%, 25/45 respectively). Premature discontinuation due to insufficient therapeutic effect was significantly lower in moxifloxacin- versus placebo-treated patients (8.2%, 6/73 vs. 22.2%, 10/45; P = .031). The rate of treatment-emergent adverse events in the ITT population was similar between arms (moxifloxacin 38.2%, 96/251; placebo 40.7%, 50/123). Although moxifloxacin 5-day therapy for ABRS was not statistically superior to placebo for the primary end point, patients who received moxifloxacin had significantly greater improvements in health outcomes and used fewer concomitant medicines than patients treated with placebo, while experiencing no increase in adverse events.


Determinants of costs and pain improvement for medical and chiropractic care of low back pain.
The purpose of this study was to identify short-term and long-term determinants of costs and pain improvement for care of low back pain (LBP) provided by medical doctors (MDs) and chiropractors (DCs). Determinants of office-based costs and pain improvement were modeled for 2872 patients with primary complaint of acute or chronic LBP of mechanical origin enrolled from practices of 111 MDs and 60 DCs using multiple regression analysis. The independent variables were baseline pain intensity (10 cm visual analog scale), chronicity (current episode > or <7 weeks), referred pain above/below the knee, history of LBP, physical health, depression screen, comorbidity, and stress index; age, sex, married, and smoker; pay variables including out-of-pocket, health insurance, auto insurance, Workers' Compensation, and Oregon Health Plan/Medicaid; and a choice of provider indicator based on relative confidence in DC and MD care. Determinants of increased office-based costs for MD care were Workers' Compensation, pain below the knee, and chronic LBP with comorbidity. Predictors of increased cost for DC care were Workers' Compensation, auto and health insurance, LBP chronicity, and baseline pain. Predictors of decreased DC cost were Medicaid and better physical health. Pain improvement was predicted consistently across groups by baseline pain, pain radiating below the knee, physical health, LBP chronicity, and chronicity by baseline pain interaction. There was also a large chronicity by comorbidity interaction at 12 months for both provider types. Cost predictors were driven by insurance type and pain improvement was driven by LBP complaint characteristics.


Chronic defects in intraspinal mechanisms of spike encoding by spinal motoneurons following chemotherapy.
Chemotherapy-induced sensorimotor disabilities, including gait and balance disorders, as well as physical fatigue often persist for months and sometimes years into disease free survival from cancer. While associated with impaired sensory function, chronic sensorimotor disorders might also depend on chemotherapy-induced defects in other neuron types. In this report, we extend consideration to motoneurons, which, if chronically impaired, would necessarily degrade movement behavior. The present study was undertaken to determine whether motoneurons qualify as candidate contributors to chronic sensorimotor disability independently from sensory impairment. We tested this possibility in vivo from rats 5 weeks following human-scaled treatment with one of the platinum-based compounds, oxaliplatin, widely used in chemotherapy for a variety of cancers. Action potential firing of spinal motoneurons responding to different fixed levels of electrode-current injection was measured in order to assess the neurons' intrinsic capacity for stimulus encoding. The encoding of stimulus duration and intensity corroborated in untreated control rats was severely degraded in oxaliplatin treated rats, in which motoneurons invariably exhibited erratic firing that was unsustained, unpredictable from one stimulus trial to the next, and unresponsive to changes in current strength. Direct measurements of interspike oscillations in membrane voltage combined with computer modeling pointed to aberrations in subthreshold conductances as a plausible contributor to impaired firing behavior. These findings authenticate impaired spike encoding as a candidate contributor to, in the case of motoneurons, deficits in mobility and fatigue. Aberrant firing also becomes a deficit worthy of testing in other CNS neurons as a potential contributor to perceptual and cognitive disorders induced by chemotherapy in patients.


Perceptual learning in an appetitive Pavlovian procedure: analysis of the effectiveness of the common element.
Non-reinforced preexposure to two stimuli often enhances discrimination between them. Analyses of this perceptual learning phenomenon have mainly focused on the role played by the distinctive stimulus features; this study examined the contribution of the non-distinctive common elements. A standard appetitive Pavlovian procedure was used. Rats received two different schedules of exposure--alternated or blocked--to two compound auditory stimuli, AX and BX. In Experiment 1 a generalization test to BX that followed conditioning to AX showed that animals responded less, and hence discriminated better, following alternated exposure, thus extending the generality of this perceptual learning effect to standard appetitive Pavlovian procedures. The degree to which the common element X was mediating this effect was explored in the next three experiments. Experiment 2 assessed the effectiveness of X following conditioning to AX. Experiment 3 explored X's effectiveness throughout extensive conditioning to X. Experiment 4 tested the ability of X to overshadow a novel stimulus Y. The results were consistent with the suggestion that alternated preexposure can reduce the relative effectiveness of the common element.


Nonreconstruction Options for Treating Medial Ulnar Collateral Ligament Injuries of the Elbow in Overhead Athletes.
This review aims to describe the nonreconstructive options for treating ulnar collateral ligament (UCL) injuries ranging from nonoperative measures, including physical therapy and biologic injections, to ligament repair with and without augmentation. Nonoperative options for UCL injuries include guided physical therapy and biologic augmentation with platelet-rich plasma (PRP). In some patients, repair of the UCL has shown promising return to sport rates by using modern suture and suture anchor techniques. Proximal avulsion injuries have shown the best results after repair. Currently, there is growing interest in augmentation of UCL repair with an internal brace. The treatment of UCL injuries involves complex decision making. UCL reconstruction remains the gold standard for attritional injuries and complete tears, which occur commonly in professional athletes. However, nonreconstructive options have shown promising results for simple avulsion or partial thickness UCL injuries. Future research comparing reconstructive versus nonreconstructive options is necessary.


Manganese and epilepsy: a systematic review of the literature.
Manganese is an essential trace element for the development and function of the central nervous system. Alterations in manganese concentrations, whether excessive or deficient, can be accompanied by convulsions. This article represents a systematic review of available quantitative evidence that might clarify this issue. We searched The Cochrane Library, Medline and LILACS databases from January 1966 through June 2006 and reviewed all resulting English and Spanish language publications, as well as those possibly relevant in other languages based on their abstracts. The final selection included for this review comprises all investigations in humans and animals that compared manganese levels in any tissue of a group with spontaneous or induced convulsions (with or without antiepileptic treatment) and a convulsion-free control group. The literature search identified thirteen publications since then relevant to the issue, four of which failed to meet our criteria for inclusion. Of the remaining nine, six were in humans and three in rodents. At present, there is no satisfactory explanation for the relationship between low manganese levels and the presence of convulsions. There is a documented correlation between low blood manganese levels and the presence of convulsions in both humans and animals. The lack of evidence indicating whether this is a cause or an effect of the convulsions clearly justifies more detailed follow-up investigations in humans.


Characterizing the Escherichia coli O157:H7 proteome including protein associations with higher order assemblies.
The recent outbreak of severe infections with Shiga toxin (Stx) producing Escherichia coli (STEC) serotype O104:H4 highlights the need to understand horizontal gene transfer among E. coli strains, identify novel virulence factors and elucidate their pathogenesis. Quantitative shotgun proteomics can contribute to such objectives, allowing insights into the part of the genome translated into proteins and the connectivity of biochemical pathways and higher order assemblies of proteins at the subcellular level. We examined protein profiles in cell lysate fractions of STEC strain 86-24 (serotype O157:H7), following growth in cell culture or bacterial isolation from intestines of infected piglets, in the context of functionally and structurally characterized biochemical pathways of E. coli. Protein solubilization in the presence of Triton X-100, EDTA and high salt was followed by size exclusion chromatography into the approximate M(r) ranges greater than 280 kDa, 280-80 kDa and 80-10 kDa. Peptide mixtures resulting from these and the insoluble fraction were analyzed by quantitative 2D-LC-nESI-MS/MS. Of the 2521 proteins identified at a 1% false discovery rate, representing 47% of all predicted E. coli O157:H7 gene products, the majority of integral membrane proteins were enriched in the high M(r) fraction. Hundreds of proteins were enriched in a M(r) range higher than that predicted for a monomer supporting their participation in protein complexes. The insoluble STEC fraction revealed enrichment of aggregation-prone proteins, including many that are part of large structure/function entities such as the ribosome, cytoskeleton and O-antigen biosynthesis cluster. Nearly all E. coli O157:H7 proteins encoded by prophage regions were expressed at low abundance levels or not detected. Comparative quantitative analyses of proteins from distinct cell lysate fractions allowed us to associate uncharacterized proteins with membrane attachment, potential participation in stable protein complexes, and susceptibility to aggregation as part of larger structural assemblies.


Consortia of anti-nematode fungi and bacteria in the rhizosphere of soybean plants attacked by root-knot nematodes.
Cyst and root-knot nematodes are major risk factors of agroecosystem management, often causing devastating impacts on crop production. The use of microbes that parasitize or prey on nematodes has been considered as a promising approach for suppressing phytopathogenic nematode populations. However, effects and persistence of those biological control agents often vary substantially depending on regions, soil characteristics and agricultural practices: more insights into microbial community processes are required to develop reproducible control of nematode populations. By performing high-throughput sequencing profiling of bacteria and fungi, we examined how root and soil microbiomes differ between benign and nematode-infected plant individuals in a soybean field in Japan. Results indicated that various taxonomic groups of bacteria and fungi occurred preferentially on the soybean individuals infected by root-knot nematodes or those uninfected by nematodes. Based on a network analysis of potential microbe-microbe associations, we further found that several fungal taxa potentially preying on nematodes (Dactylellina (Orbiliales), Rhizophydium (Rhizophydiales), Clonostachys (Hypocreales), Pochonia (Hypocreales) and Purpureocillium (Hypocreales)) co-occurred in the soybean rhizosphere at a small spatial scale. This study suggests how 'consortia' of anti-nematode microbes can derive from indigenous (resident) microbiomes, providing basic information for managing anti-nematode microbial communities in agroecosystems.


Differential virulence and pathogenesis of West Nile viruses.
West Nile virus (WNV) is a neurotropic flavivirus that cycles between mosquitoes and birds but that can also infect humans, horses, and other vertebrate animals. In most humans, WNV infection remains subclinical. However, 20%-40% of those infected may develop WNV disease, with symptoms ranging from fever to meningoencephalitis. A large variety of WNV strains have been described worldwide. Based on their genetic differences, they have been classified into eight lineages; the pathogenic strains belong to lineages 1 and 2. Ten years ago, Beasley et al. (2002) found that dramatic differences exist in the virulence and neuroinvasion properties of lineage 1 and lineage 2 WNV strains. Further insights on how WNV interacts with its hosts have recently been gained; the virus acts either at the periphery or on the central nervous system (CNS), and these observed differences could help explain the differential virulence and neurovirulence of WNV strains. This review aims to summarize the current state of knowledge on factors that trigger WNV dissemination and CNS invasion as well as on the inflammatory response and CNS damage induced by WNV. Moreover, we will discuss how WNV strains differentially interact with the innate immune system and CNS cells, thus influencing WNV pathogenesis.


Correlation of respiratory oscillometry with CT image analysis in a prospective cohort of idiopathic pulmonary fibrosis.
Markers of idiopathic pulmonary fibrosis (IPF) severity are based on measurements of forced vital capacity (FVC), diffusing capacity (DLCO) and CT. The pulmonary vessel volume (PVV) is a novel quantitative and independent prognostic structural indicator derived from automated CT analysis. The current prospective cross-sectional study investigated whether respiratory oscillometry provides complementary data to pulmonary function tests (PFTs) and is correlated with PVV. From September 2019 to March 2020, we enrolled 89 patients with IPF diagnosed according to international guidelines. We performed standard spectral (5-37 Hz) and novel intrabreath tracking (10 Hz) oscillometry followed by PFTs. Patients were characterised with the gender-age-physiology (GAP) score. CT images within 6 months of oscillometry were analysed in a subgroup (26 patients) using automated lung texture analysis. Correlations between PFTs, oscillometry and imaging variables were investigated using different regression models. The cohort (29F/60M; age=71.7±7.8 years) had mild IPF (%FVC=70±17, %DLCO=62±17). Spectral oscillometry revealed normal respiratory resistance, low reactance, especially during inspiration at 5 Hz (X5in), elevated reactance area and resonance frequency. Intrabreath oscillometry identified markedly low reactance at end-inspiration (XeI). XeI and X5in strongly correlated with FVC (r2=0.499 and 0.435) while XeI was highly (p=0.004) and uniquely correlated with the GAP score. XeI and PVV exhibited the strongest structural-functional relationship (r2=0.690), which remained significant after adjusting for %FVC, %DLCO and GAP score. XeI is an independent marker of IPF severity that offers additional information to standard PFTs. The data provide a cogent rationale for adding oscillometry in IPF assessment.


Programmed cell death in the nematode C. elegans.
Programmed cell death is a common feature during animal development. In the nematode C. elegans, more than 12 genes have been identified that function in the apoptotic killing and elimination of 131 of the 1090 cells that are generated during hermaphrodite development. These genes divide the process of programmed cell death into three distinct steps: execution of the death sentence; engulfment of dying cells; and degradation of dead, engulfed cells. Biochemical characterization of the genes in this pathway has led to the identification of an apoptotic machinery that mediates apoptotic death in this species. The proximal cause of apoptosis in C. elegans is the activation of the caspase homolog CED-3 from the inactive zymogen (proCED-3) into the mature protease. This activation is mediated by the Apaf-1 homolog CED-4. In cells that should survive, CED-3 and CED-4 pro-apoptotic activity is antagonized by the Bcl-2 family member CED-9. CED-9 has been proposed to prevent death by sequestering CED-4 and proCED-3 in an inactive ternary complex, the apoptosome. In cells fated to die, CED-9 is, in turn, inactivated by the pro-apoptotic BH3 domain-containing protein EGL-1, likely through a direct protein-protein interaction. The structural and functional conservation of cell death genes between nematodes and mammals strongly suggests that the apoptotic program is ancient in origin and that all metazoans share a common mechanism of apoptotic cell killing.


Effectiveness of cognitive behavior therapy for severe mood disorders in an acute psychiatric naturalistic setting: a benchmarking study.
The current study examined the effectiveness of brief cognitive behavior therapy (CBT) for severe mood disorders in an acute naturalistic setting. The sample included 951 individuals with either major depressive disorder (n = 857) or bipolar disorder with depressed mood (n = 94). Participants completed a battery of self-report measures assessing depression, overall well-being, and a range of secondary outcomes both before and after treatment. We found significant reductions in depressive symptoms, worry, self-harm, emotional lability, and substance abuse, as well as significant improvements in well-being and interpersonal relationships, post-treatment. Comparable to outpatient studies, 30% of the sample evidenced recovery from depression. Comparison of findings to benchmark studies indicated that, although the current sample started treatment with severe depressive symptoms and were in treatment for average of only 10 days, the overall magnitude of symptom improvement was similar to that of randomized controlled trials. Limitations of the study include a lack of control group, a limitation of most naturalistic studies. These findings indicate that interventions developed in controlled research settings on the efficacy of CBT can be transported to naturalistic, "real world" settings, and that brief CBT delivered in a partial hospital program is effective for many patients with severe depressive symptoms.


[Factors associated with short duration of breast-feeding in Mexican working women].
To identify the maternal, work, and health services factors associated with a short duration of breast-feeding in working mothers. A cross-sectional study was carried out between November 1998 and March 1999, among 265 mothers medically insured by (Instituto Mexicano del Seguro Social, IMSS) Mexican Institute of Social Security, who completed a questionnaire when their babies were 3 to 9 months old. Mothers were divided into two groups, based on breast-feeding duration: those who breast-fed for less than 3 months and those who did so for three months or more. Logistic regression was used to identify the factors associated with short duration of breast-feeding. One-hundred and twelve mothers (42.3%) abandoned breast-feeding early. Risk factors were: poor maternal knowledge on breast-feeding, odds ratio (OR) 5.97, 95% confidence interval (CI) 1.67-20.67; mothers with no previous breast-feeding experience OR 2.98, 95% CI 1.66-5.36; mothers planning to breast-feed their babies for less than 3 months (OR 16.24, 95% CI 5.37-49.12); and mothers with no access to breast-feeding facilities at work (OR 1.99, 95% CI 1.12-3.56). The main factors associated with short duration of breast-feeding were the maternal ones. The only work-related factor associated with short duration of breast-feeding was the absence of breast-feeding facilities. It is probable that maternal knowledge on breast-feeding, previous breast-feeding experience, and the availability of facilities at work for breast-feeding affect the maternal decisions on breast-feeding duration.


An accurate multi-channel multi-reference full-dimensional global potential energy surface for the lowest triplet state of H2O2.
The lowest triplet state of the H2O2 system features multiple reaction channels, including several relevant to the combustion of H2. To accurately map out the global potential energy surface, ∼28 000 geometries were sampled over a large configuration space including all important asymptotes, and electronic energies at these points were calculated at the level of the explicitly correlated version of the multi-reference configuration interaction (MRCI-F12) method. A new multi-channel global potential energy surface was constructed by fitting the ab initio data set using a permutation invariant polynomial-neural network method, resulting in a total root mean square fitting error of only 6.7 meV (0.15 kcal mol-1). Various kinetics and dynamical properties of several relevant reactions were calculated on the new MRCI potential energy surface, and compared with the available experimental results.


Proteomic analysis of ubiquitinated proteins in normal hepatocyte cell line Chang liver cells.
Post-translational modification by ubiquitin (Ub) and Ub-like modifiers is one of the most important mechanisms regulating a wide range of cellular processes in eukaryotes. Through mediating 26S proteasome-dependent degradation of substrates, the covalent modification of proteins by multiple Ub (ubiquitination) can regulate many different cellular functions such as transcription, antigen processing, signal transduction and cell cycle. To better understand ubiquitination and its functions, proteomic approaches have been developed to purify and identify more protein substrates. The S5a subunit of the 26S proteasome binds to poly-Ub chains containing four or more Ub. In this study, immobilized GST-S5a fusion protein was used to affinity-purify ubiquitinated proteins from Chang liver cells. The purified proteins were then identified with multi-dimensional LC combined with MS/MS. Eighty-three potential ubiquitination substrates were identified. From these proteins, 19 potential ubiquitination sites on 17 potential substrates were determined. These potential ubiquitination substrates are mainly related to important cellular functions including metabolism, translation and transcription. Our results provide helpful information for further understanding of the relationship between ubiquitination machinery and different cell functions.


A probabilistic model for reducing medication errors.
Medication errors are common, life threatening, costly but preventable. Information technology and automated systems are highly efficient for preventing medication errors and therefore widely employed in hospital settings. The aim of this study was to construct a probabilistic model that can reduce medication errors by identifying uncommon or rare associations between medications and diseases. Association rules of mining techniques are utilized for 103.5 million prescriptions from Taiwan's National Health Insurance database. The dataset included 204.5 million diagnoses with ICD9-CM codes and 347.7 million medications by using ATC codes. Disease-Medication (DM) and Medication-Medication (MM) associations were computed by their co-occurrence and associations' strength were measured by the interestingness or lift values which were being referred as Q values. The DMQs and MMQs were used to develop the AOP model to predict the appropriateness of a given prescription. Validation of this model was done by comparing the results of evaluation performed by the AOP model and verified by human experts. The results showed 96% accuracy for appropriate and 45% accuracy for inappropriate prescriptions, with a sensitivity and specificity of 75.9% and 89.5%, respectively. We successfully developed the AOP model as an efficient tool for automatic identification of uncommon or rare associations between disease-medication and medication-medication in prescriptions. The AOP model helps to reduce medication errors by alerting physicians, improving the patients' safety and the overall quality of care.


Synthesis, characterization and in vitro cytotoxicity studies of poly-N-isopropyl acrylamide gel nanoparticles and films.
In this work, we show synthesis that leads to thermoreponsive poly-N-isopropyl acrylamide (pNIPAM) nanogels with sizes below 100 nm, irrespectively of the surfactant to crosslinker ratio. We also show that in many environments the temperature induced pNIPAM collapse at Lower Critical Solution Temperature (LCST) of 32.5 °C is accompanied by gel nanoparticles' aggregation. Thus, the proper information on the nanoparticle (NP) structure and deswelling can be obtained only if the routinely measured hydrodynamic radius is supplemented by information on the molecular weight, which can be obtained from the intensity of scattered light. We measured the dynamics and reversibility of the deswelling and subsequent aggregation processes. Furthermore, we show that the highly concentrated pNIPAM gel NPs reversibly form bulk hydrogel networks of varied interconnected porous structure. We show, that in case of drying pNIPAM gel NPs above the LCST, it is possible to obtain films with 20-fold increase in storage modulus (G') compared to hydrogel networks measured at room temperature. They exhibit temperature hysteresis behavior around LCST of 32.5 °C similar to pNIPAM films. Finally, we show that these hydrogel films, lead to extended proliferation of cells across three different types: fibroblast, endothelial and cancer cells. Additionally, none of the films exhibited any cytotoxic effects. Our study brings new insights into physicochemical characterization of pNIPAM gel NPs and networks behavior in realistic conditions of in vitro measurements, especially by means of dynamic light scattering as well as final unique properties of both gel NPs and formed porous films for possible tissue engineering applications.


Proteomic and transcriptomic analyses of "Candidatus Pelagibacter ubique" describe the first PII-independent response to nitrogen limitation in a free-living Alphaproteobacterium.
Nitrogen is one of the major nutrients limiting microbial productivity in the ocean, and as a result, most marine microorganisms have evolved systems for responding to nitrogen stress. The highly abundant alphaproteobacterium "Candidatus Pelagibacter ubique," a cultured member of the order Pelagibacterales (SAR11), lacks the canonical GlnB, GlnD, GlnK, and NtrB/NtrC genes for regulating nitrogen assimilation, raising questions about how these organisms respond to nitrogen limitation. A survey of 266 Alphaproteobacteria genomes found these five regulatory genes nearly universally conserved, absent only in intracellular parasites and members of the order Pelagibacterales, including "Ca. Pelagibacter ubique." Global differences in mRNA and protein expression between nitrogen-limited and nitrogen-replete cultures were measured to identify nitrogen stress responses in "Ca. Pelagibacter ubique" strain HTCC1062. Transporters for ammonium (AmtB), taurine (TauA), amino acids (YhdW), and opines (OccT) were all elevated in nitrogen-limited cells, indicating that they devote increased resources to the assimilation of nitrogenous organic compounds. Enzymes for assimilating amine into glutamine (GlnA), glutamate (GltBD), and glycine (AspC) were similarly upregulated. Differential regulation of the transcriptional regulator NtrX in the two-component signaling system NtrY/NtrX was also observed, implicating it in control of the nitrogen starvation response. Comparisons of the transcriptome and proteome supported previous observations of uncoupling between transcription and translation in nutrient-deprived "Ca. Pelagibacter ubique" cells. Overall, these data reveal a streamlined, PII-independent response to nitrogen stress in "Ca. Pelagibacter ubique," and likely other Pelagibacterales, and show that they respond to nitrogen stress by allocating more resources to the assimilation of nitrogen-rich organic compounds. Pelagibacterales are extraordinarily abundant and play a pivotal role in marine geochemical cycles, as one of the major recyclers of labile dissolved organic matter. They are also models for understanding how streamlining selection can reshape chemoheterotroph metabolism. Streamlining and its broad importance to environmental microbiology are emerging slowly from studies that reveal the complete genomes of uncultured organisms. Here, we report another remarkable example of streamlined metabolism in Pelagibacterales, this time in systems that control nitrogen assimilation. Pelagibacterales are major contributors to metatranscriptomes and metaproteomes from ocean systems, where patterns of gene expression are used to gain insight into ocean conditions and geochemical cycles. The data presented here supply background that is essential to interpreting data from field studies.


Increasing coverage and decreasing inequity in insecticide-treated bed net use among rural Kenyan children.
Inexpensive and efficacious interventions that avert childhood deaths in sub-Saharan Africa have failed to reach effective coverage, especially among the poorest rural sectors. One particular example is insecticide-treated bed nets (ITNs). In this study, we present repeat observations of ITN coverage among rural Kenyan homesteads exposed at different times to a range of delivery models, and assess changes in coverage across socioeconomic groups. We undertook a study of annual changes in ITN coverage among a cohort of 3,700 children aged 0-4 y in four districts of Kenya (Bondo, Greater Kisii, Kwale, and Makueni) annually between 2004 and 2006. Cross-sectional surveys of ITN coverage were undertaken coincidentally with the incremental availability of commercial sector nets (2004), the introduction of heavily subsidized nets through clinics (2005), and the introduction of free mass distributed ITNs (2006). The changing prevalence of ITN coverage was examined with special reference to the degree of equity in each delivery approach. ITN coverage was only 7.1% in 2004 when the predominant source of nets was the commercial retail sector. By the end of 2005, following the expansion of heavily subsidized clinic distribution system, ITN coverage rose to 23.5%. In 2006 a large-scale mass distribution of ITNs was mounted providing nets free of charge to children, resulting in a dramatic increase in ITN coverage to 67.3%. With each subsequent survey socioeconomic inequity in net coverage sequentially decreased: 2004 (most poor [2.9%] versus least poor [15.6%]; concentration index 0.281); 2005 (most poor [17.5%] versus least poor [37.9%]; concentration index 0.131), and 2006 with near-perfect equality (most poor [66.3%] versus least poor [66.6%]; concentration index 0.000). The free mass distribution method achieved highest coverage among the poorest children, the highly subsidised clinic nets programme was marginally in favour of the least poor, and the commercial social marketing favoured the least poor. Rapid scaling up of ITN coverage among Africa's poorest rural children can be achieved through mass distribution campaigns. These efforts must form an important adjunct to regular, routine access to ITNs through clinics, and each complimentary approach should aim to make this intervention free to clients to ensure equitable access among those least able to afford even the cost of a heavily subsidized net.


An attachment theory perspective in the examination of relational processes associated with coach-athlete dyads.
The aim of the current study was to examine actor and partner effects of (a) athletes' and coaches' attachment styles (avoidant and anxious) on the quality of the coach-athlete relationship, and (b) athletes' and coaches' quality of the coach-athlete relationship on relationship satisfaction employing the actor-partner interdependence model (Kenny, Kashy, & Cook, 2006). Coaches (N = 107) and athletes (N = 107) completed a questionnaire related to attachment styles, relationship quality, and relationship satisfaction. Structural equation model analyses revealed (a) actor effects for coaches' and athletes' avoidant attachment styles on their own perception of relationship quality and coaches' and athletes' perception of relationship quality on their own perception of relationship satisfaction, and (b) partner effects for athletes' avoidant attachment style on coaches' perceptions of relationship quality and for coaches' perceptions of relationship quality on athletes' perceptions of relationship satisfaction. The findings highlight that attachments styles can help us understand the processes involved in the formation and maintenance of quality relational bonds between coaches and athletes.


Genomic and biochemical characterization of sialic acid acetylesterase (siae) in zebrafish.
Sialic acid acetylesterase (SIAE) removes acetyl moieties from the carbon 9 and 4 hydroxyl groups of sialic acid and recently a debate has been opened on its association to autoimmunity. Trying to get new insights on this intriguing enzyme we have studied siae in zebrafish (Danio rerio). In this teleost siae encodes for a polypeptide with a high degree of sequence identity to human and mouse counterparts. Zebrafish Siae behavior upon transient expression in COS7 cells is comparable to human enzyme concerning pH optimum of enzyme activity, subcellular localization and glycosylation. In addition, and as already observed in case of human SIAE, the glycosylated form of the enzyme from zebrafish is released into the culture media. During embryogenesis, in situ hybridization experiments demonstrate that siae transcript is always detectable during development, with a more specific expression in the central nervous system, in pronephric ducts and liver in the more advanced stages of the embryo development. In adult fish an increasing amount of siae mRNA is detectable in heart, eye, muscle, liver, brain, kidney and ovary. These results provide novel information about Siae and point out zebrafish as animal model to better understand the biological role(s) of this rather puzzling enzyme in vertebrates, regarding immune system function and the development of central nervous system.


Electronic cigarettes increase endothelial progenitor cells in the blood of healthy volunteers.
The use of electronic cigarettes is increasing dramatically on a global scale and its effects on human health remain uncertain. In the present study, we measured endothelial progenitor cells (EPCs) and microvesicles (MVs) in healthy young volunteers following short-term exposure to inhalation of e-cigarette vapor (ECV) to determine vascular changes. Sixteen healthy seldom smokers were randomized into two groups either exposed or not exposed to 10 puffs of ECV for 10 min, in a crossover design. Blood samples were obtained at baseline and 1, 4 and 24 h following exposure. EPCs (CD34 + CD309) and MVs were analyzed by flow cytometry. MVs were phenotyped according to origin (platelet (CD41), endothelial (CD144), leukocytes (CD45), monocytes (CD14)) and nuclear content (SYTO 13 dye). In addition, expression of inflammation markers such P-selectin (CD62P), E-selectin (CD62E), CD40-ligand (CD154) and HMGB1 was investigated. Fractional exhaled nitric oxide (FeNO) was also measured at baseline and after 24 h. EPC levels in blood were significantly increased 1 h following exposure to ECV and returned to baseline values after 24 h. Only E-selectin positive MVs (endothelial origin) were slightly elevated (p < 0.038). FeNO was unaffected by exposure to ECV. In healthy volunteers, ten puffs of e-cigarette vapor inhalation caused an increase in EPCs. This increase was of the same magnitude as following smoking of one traditional cigarette, as we previously demonstrated. Taken together, these results may represent signs of possible vascular changes after short e-cigarette inhalation. Further studies analyzing potential cardiovascular health effects are critical as the e-cigarette market continues to burgeon.


Complement-containing small extracellular vesicles from adventitial fibroblasts induce proinflammatory and metabolic reprogramming in macrophages.
Pulmonary hypertension (PH) is a severe cardiopulmonary disease characterized by complement-dependent, fibroblast-induced perivascular accumulation and proinflammatory activation of macrophages. We hypothesized that, in PH, nanoscale-sized small extracellular vesicles (sEVs), released by perivascular/adventitial fibroblasts, are critical mediators of complement-dependent proinflammatory activation of macrophages. Pulmonary adventitial fibroblasts were isolated from calves with severe PH (PH-Fibs) and age-matched controls (CO-Fibs). PH-Fibs exhibited increased secretion of sEVs, compared with CO-Fibs, and sEV biological activity was tested on mouse and bovine bone marrow-derived macrophages (BMDMs) and showed similar responses. Compared with sEVs derived from CO-Fibs, sEVs derived from PH-Fibs (PH-Fib-sEVs) induced augmented expression of proinflammatory cytokines/chemokines and metabolic genes in BMDMs. Pharmacological blockade of exosome release from PH-Fibs resulted in significant attenuation of proinflammatory activation of BMDMs. "Bottom-up" proteomic analyses revealed significant enrichment of complement and coagulation cascades in PH-Fib-sEVs, including augmented expression of the complement component C3. We therefore examined whether the PH-Fib-sEV-mediated proinflammatory activation of BMDMs was complement C3 dependent. Treatment of PH-Fibs with siC3-RNA significantly attenuated the capacity of PH-Fib-sEVs for proinflammatory activation of BMDMs. PH-Fib-sEVs mediated proglycolytic alterations and complement-dependent activation of macrophages toward a proinflammatory phenotype, as confirmed by metabolomic studies. Thus, fibroblast-released sEVs served as critical mediators of complement-induced perivascular/microenvironmental inflammation in PH.


Seminal fluid of honeybees contains multiple mechanisms to combat infections of the sexually transmitted pathogen Nosema apis.
The societies of ants, bees and wasps are genetically closed systems where queens only mate during a brief mating episode prior to their eusocial life and males therefore provide queens with a lifetime supply of high-quality sperm. These ejaculates also contain a number of defence proteins that have been detected in the seminal fluid but their function and efficiency have never been investigated in great detail. Here, we used the honeybee Apis mellifera and quantified whether seminal fluid is able to combat infections of the fungal pathogen Nosema apis, a widespread honeybee parasite that is also sexually transmitted. We provide the first empirical evidence that seminal fluid has a remarkable antimicrobial activity against N. apis spores and that antimicrobial seminal fluid components kill spores in multiple ways. The protein fraction of seminal fluid induces extracellular spore germination, which disrupts the life cycle of N. apis, whereas the non-protein fraction of seminal fluid induces a direct viability loss of intact spores. We conclude that males provide their ejaculates with efficient antimicrobial molecules that are able to kill N. apis spores and thereby reduce the risk of disease transmission during mating. Our findings could be of broader significance to master honeybee diseases in managed honeybee stock in the future.


Langerhans cells require MyD88-dependent signals for Candida albicans response but not for contact hypersensitivity or migration.
Langerhans cells (LC) are a subset of skin-resident dendritic cells (DC) that reside in the epidermis as immature DC, where they acquire Ag. A key step in the life cycle of LC is their activation into mature DC in response to various stimuli, including epicutaneous sensitization with hapten and skin infection with Candida albicans. Mature LC migrate to the skin-draining LN, where they present Ag to CD4 T cells and modulate the adaptive immune response. LC migration is thought to require the direct action of IL-1β and IL-18 on LC. In addition, TLR ligands are present in C. albicans, and hapten sensitization produces endogenous TLR ligands. Both could contribute to LC activation. We generated Langerin-Cre MyD88(fl) mice in which LC are insensitive to IL-1 family members and most TLR ligands. LC migration in the steady state, after hapten sensitization and postinfection with C. albicans, was unaffected. Contact hypersensitivity in Langerin-Cre MyD88(fl) mice was similarly unaffected. Interestingly, in response to C. albicans infection, these mice displayed reduced proliferation of Ag-specific CD4 T cells and defective Th17 subset differentiation. Surface expression of costimulatory molecules was intact on LC, but expression of IL-1β, IL-6, and IL-23 was reduced. Thus, sensitivity to MyD88-dependent signals is not required for LC migration, but is required for the full activation and function of LC in the setting of fungal infection.


Applying the WHO recommendations on health-sector response to violence against women to assess the Spanish health system. A mixed methods approach.
This methodological note describes the development and application of a mixed-methods protocol to assess the responsiveness of Spanish health systems to violence against women in Spain, based on the World Health Organization (WHO) recommendations. Five areas for exploration were identified based on the WHO recommendations: policy environment, protocols, training, accountability/monitoring, and prevention/promotion. Two data collection instruments were developed to assess the situation of 17 Spanish regional health systems (RHS) with respect to these areas: 1) a set of indicators to guide a systematic review of secondary sources, and 2) an interview guide to be used with 26 key informants at the regional and national levels. We found differences between RHSs in the five areas assessed. The progress of RHSs on the WHO recommendations was notable at the level of policies, moderate in terms of health service delivery, and very limited in terms of preventive actions. Using a mixed-methods approach was useful for triangulation and complementarity during instrument design, data collection and interpretation.


New isoelectric buffers for capillary electrophoresis: N-carboxymethylated polyethyleneimine as a macromolecular isoelectric buffer.
Isoelectric buffers are attractive for electrophoresis because of their low conductivity, and their compatibility with indirect photometric detection in capillary electrophoresis (CE) where they do not interfere with the detection by exhibiting competitive displacement of the UV-absorbing probe ion. N-carboxymethylated polyethyleneimine (CMPEI) was prepared by introducing a half molar equivalent of carboxylate groups onto a polyethyleneimine backbone. Its isoelectric point determined by conductometric titration and from the pH of its dilute aqueous solution is approx. 6.8, which allows isoelectric buffering at a lower pH compared to histidine (pI7.7). Although the isoelectric point is somewhat diffuse, as expected for a polymeric compound, it exhibits a buffering capacity at a pI point of about twice that of histidine. Studies of electroosmotic flow (EOF) profile at various pH values in fused silica capillaries showed that CMPEI adsorbs onto the fused silica wall and reverses the EOF at pH < 6.5. CMPEI was applied as a buffer in an electrolyte containing 0.5 mM of the anionic dye tartrazine used as the probe for indirect detection of anions. The separation system exhibited a stable baseline, no system peaks, separation efficiencies of up to 195,000 theoretical plates, and detection limits down to 0.2 microM or 2 amol of injected analyte.


The structure of male adolescent peer networks and risk for intimate partner violence perpetration: findings from a national sample.
Although peer networks have been implicated as influential in a range of adolescent behaviors, little is known about relationships between peer network structures and risk for intimate partner violence (IPV) among youth. This study is a descriptive analysis of how peer network "types" may be related to subsequent risk for IPV perpetration among adolescents using data from 3,030 male respondents to the National Longitudinal Study of Adolescent Health. Sampled youth were a mean of 16 years of age when surveyed about the nature of their peer networks, and 21.9 when asked to report about IPV perpetration in their adolescent and early adulthood relationships. A latent class analysis of the size, structure, gender composition and delinquency level of friendship groups identified four unique profiles of peer network structures. Men in the group type characterized by small, dense, mostly male peer networks with higher levels of delinquent behavior reported higher rates of subsequent IPV perpetration than men whose adolescent network type was characterized by large, loosely connected groups of less delinquent male and female friends. Other factors known to be antecedents and correlates of IPV perpetration varied in their distribution across the peer group types, suggesting that different configurations of risk for relationship aggression can be found across peer networks. Implications for prevention programming and future research are addressed.


Meta-Analysis Comparing Direct Oral Anticoagulants Versus Warfarin in Morbidly Obese Patients With Atrial Fibrillation.
The International Society of Thrombosis and Haemostasis recommends warfarin therapy over direct oral anticoagulants (DOACs) in patients with a body mass index >40 kg/m2 or weight > 120 kg due to limited clinical data in morbidly obese patients. The aim of the meta-analysis was to compare DOACs with warfarin in morbidly obese patients with atrial fibrillation (AF) and to optimize an anticoagulation therapy in the population. MEDLINE, Embase, Google Scholar, Web of Science, and Cochrane Library database searches for relevant articles through December 23, 2019 were performed. Total 5 studies for the event rate of stroke or systemic embolism (SE) and 4 studies for major bleeding were included in the meta-analysis. It showed that there was no statistically significant difference in stroke or SE event rate between the DOAC and warfarin groups (odds ratio: 0.85; 95% confidence interval: 0.60, 1.19; p = 0.35; I2 = 0 %). The DOAC use was significantly associated with a lower major bleeding event rate compared the warfarin group (odds ratio: 0.63; 95% confidence interval: 0.43, 0.94; p = 0.02; I2 = 30%). In conclusion, DOACs should be considered as an oral anticoagulant for preventing stroke or SE in morbidly obese patients with AF. A randomized controlled trial comparing a DOAC with warfarin is needed to confirm our meta-analysis results in morbidly obese patients with AF.


'The Art of Understanding in Forensic Psychiatric Care' - From a Caring Science Perspective Based on a Lifeworld Approach.
Patients in forensic psychiatric clinics are a vulnerable and exposed patient group due to suffering from a severe mental disorder, having committed a crime and being cared for against their will in an institutional environment with a high level of security. The art of understanding in forensic psychiatric care is discussed from a caring science perspective, based on a lifeworld approach. The aim is to contribute knowledge that can support staff, who daily meet patients on forensic psychiatric wards, in applying a caring attitude.


Proton pump inhibitor-associated pneumonia: Not a breath of fresh air after all?
Over the past two decades, proton pump inhibitors (PPIs) have emerged as highly effective and relatively safe agents for the treatment of a variety of gastrointestinal disorders. Unfortunately, this desirable pharmacological profile has also contributed to superfluous and widespread use in both the inpatient and outpatient settings. While generally well-tolerated, research published over the last decade has associated these agents with increased risks of Clostridium difficile disease, fractures likely due to calcium malabsorption and both community-acquired (CAP) and hospital-acquired pneumonias (HAP). The mechanism behind PPI-associated pneumonia may be multifactorial, but is thought to stem from compromising the stomach's "acid mantle" against gastric colonization of acid-labile pathogenic bacteria which then may be aspirated. A secondary postulate is that PPIs, through their inhibition of extra-gastric H(+)/K(+)-ATPase enzymes, may reduce the acidity of the upper aerodigestive tract, thus resulting in increased bacterial colonization of the larynx, esophagus and lungs. To date, several retrospective case control studies have been published looking at the association between PPI use and CAP. Some studies found a temporal relationship between PPI exposure and the incidence of pneumonia, but only two could define a dose-response relationship. Furthermore, other studies found an inverse correlation between duration of PPI use and risk of CAP. In terms of HAP, we reviewed two retrospective cohort studies and one prospective study. One retrospective study in a medical ICU found no increased association of HAP in PPI-exposed patients compared to no acid-lowering therapy, while the other in cardiothoracic surgery patients showed a markedly increased risk compared to those receiving H(2)RAs. The one prospective study in ICU patients showed an increased risk of HAP with PPIs, but not with H(2)RAs. In conclusion, the current literature shows a slight trend toward an association between PPI use and pneumonia and an increased risk with PPIs over H(2)RAs, but the findings are not consistent across all studies. Larger controlled trials still need to be done to better identify the risk that PPIs impart towards patients contracting CAP or HAP. Until these are completed, we will have to continue to extrapolate across smaller controlled trials to predict the associated risks in our respective patient populations. In the interim, it appears prudent to limit the use of PPIs to situations where they are clinically indicated and, in such cases, use them at the lowest effective dose. In the case of prescribing for stress ulcer prophylaxis in ICU patients, perhaps H(2)RAs should be used as the preferred agents over PPIs.


Awareness and implementation of nine World Health Organization's patient safety solutions among three groups of healthcare workers in Oman.
The pressing need to reduce burgeoning poor safety measures affecting millions worldwide has alerted World Health Assembly to set-up mechanisms to increase patient safety. In response to such needs, World Health Organization (WHO) formulated nine life-saving patient safety solutions that would be essential to lower reduce healthcare-related harm. There is a paucity of research examining awareness of such nine patient safety solutions. This study has been designed and conducted to compare self-estimated awareness and practice of the World Health Organization's nine "Life-saving Patient Safety Solutions" aide memoirs among different groups of healthcare workers in Oman. All nationwide healthcare workers (nurses, physicians and allied health professionals) in hospitals and primary healthcare under the auspice of Ministry of Health were the target population of this survey. Participants were selected by a simple, systematic random sampling from the list of staff in each representative institution. The study was conducted from November 2012 to February 2013. A total of 800 participants (590 from health centers and 210 from hospitals) were invited to participate in this study. A total number of 763 healthcare professionals consented to participate. The overall response rate was 95 % with the majority being nurses, female staff and who had an average of more than 4 years of experience. Overall, 85 % of the participants self-estimated awareness of the nine life-saving patient safety solutions showed the nurses being the most aware, followed by physicians with the allied health professionals showing suboptimal awareness. The primary healthcare center staff demonstrated higher awareness compared to hospital staff. There was a complex relationship between health professional's age, place of work and awareness and practice. This study lays the foundation for international comparisons of self-estimated awareness and practice towards nine patient safety solutions. The data from Oman indicates the need for more attention to be directed towards heightening awareness and practice of the nine patient safety solutions.


Foot massage versus quiet presence on agitation and mood in people with dementia: a randomised controlled trial.
There is increasing interest in using complementary and alternative treatments to manage behavioural and psychological symptoms of dementia such as agitation, aggression and depressed mood. To compare the effect of foot massage (intervention) and quiet presence (control) on agitation and mood in people with dementia. A randomised controlled trial using a within-subjects, crossover design. Five long-term care facilities in Brisbane, Australia. The primary outcome was the Cohen-Mansfield Agitation Inventory (CMAI) and the secondary outcome was the Observed Emotion Rating Scale (OERS). The screening and data collection research assistants, families, and care staff were blinded to participant allocation. Participants of the study were 55 long-term care residents aged 74-103 years (mean age 86.5), with moderate to severe dementia and a history of agitated behaviour according to the Pittsburgh Agitation Scale. A computer-program randomised participants to 10-min foot massage (intervention) or quiet presence (control), every weekday for 3 weeks. A carry-over effect was identified in the data, and so the data was treated as a parallel groups RCT. The mean total CMAI increased in both groups (reflecting an increase in agitation) with this increase greater in the quiet presence group than the foot massage group (p=0.03). There was a trend towards a difference on OERS General Alertness, with a positive change in alertness for participants in the foot massage group (indicating reduced alertness) and a negative change for participants in the quiet presence group (indicating increased alertness) (F(1,51)=3.88, p=0.05, partial ή(2)=0.07). The findings highlight the need for further research on the specific conditions under which massage might promote relaxation and improve mood for people with dementia. The unfamiliar research assistants and variations in usual activity may have contributed to the increase in agitation and this needs further research. ACTRN12612000658819.


Acute effects of triazolam and lorazepam on human learning, performance and subject ratings.
Triazolam (0,0.125, 0.25, 0.5, and 0.75 mg/70 kg) and lorazepam (0, 1, 2, 4 and 6 mg/70 kg) were compared in eight healthy men by using a double-blind, crossover design. Triazolam was chosen for study to examine experimentally whether it produces greater behavioral impairment than other benzodiazepines as reported previously. Lorazepam was chosen as the comparison drug because of its well documented behavioral effects and because it has a short metabolic half-life and no active metabolite, which eliminates the possible confounding effects of drug accumulation. Drug effects were assessed before and every 30 min for 8 hr after drug administration. Learning was chosen for study because it is a fundamental component of more complex behavioral processes such as recall, and benzodiazepines are known to disrupt learning. A psychomotor task and subject-rating scales, assessing drug effects and abuse potential, were also included to provide a more comprehensive comparison of these compounds. Triazolam and lorazepam dose-dependently disrupted learning and psychomotor performance and increased subject ratings of sedation to a comparable degree. These findings do not support allegations that triazolam produces greater behavioral impairment than other commonly used benzodiazepines.


Airway epithelial wounds in rhesus monkey generate ionic currents that guide cell migration to promote healing.
Damage to the respiratory epithelium is one of the most critical steps to many life-threatening diseases, such as acute respiratory distress syndrome and chronic obstructive pulmonary disease. The mechanisms underlying repair of the damaged epithelium have not yet been fully elucidated. Here we provide experimental evidence suggesting a novel mechanism for wound repair: endogenous electric currents. It is known that the airway epithelium maintains a voltage difference referred to as the transepithelial potential. Using a noninvasive vibrating probe, we demonstrate that wounds in the epithelium of trachea from rhesus monkeys generate significant outward electric currents. A small slit wound produced an outward current (1.59 μA/cm(2)), which could be enhanced (nearly doubled) by the ion transport stimulator aminophylline. In addition, inhibiting cystic fibrosis transmembrane conductance regulator (CFTR) with CFTR(Inh)-172 significantly reduced wound currents (0.17 μA/cm(2)), implicating an important role of ion transporters in wound induced electric potentials. Time-lapse video microscopy showed that applied electric fields (EFs) induced robust directional migration of primary tracheobronchial epithelial cells from rhesus monkeys, towards the cathode, with a threshold of <23 mV/mm. Reversal of the field polarity induced cell migration towards the new cathode. We further demonstrate that application of an EF promoted wound healing in a monolayer wound healing assay. Our results suggest that endogenous electric currents at sites of tracheal epithelial injury may direct cell migration, which could benefit restitution of damaged airway mucosa. Manipulation of ion transport may lead to novel therapeutic approaches to repair damaged respiratory epithelium.


Fibromyalgia: gender differences and sleep-disordered breathing.
The prevalence of fibromyalgia (FM) is much lower in men than in women. Therefore, current knowledge about this chronic pain syndrome emerged mainly from research on women. The aim of the present study was to compare clinical symptoms and sleep parameters between male and female FM patients. Forty FM patients (18 men and 22 women) aged 48.00±8.45 years were evaluated with questionnaires on pain, sleep, fatigue, depression, anxiety and functional impact, and polysomnography (PSG). 61% of male FM patients had an apnea-hypopnea index (AHI) greater than 15, compared to 31.8% of women, and a desaturation index (DI) above five, which was twice more prevalent in men than in women. In addition, males had poorer sleep quality (16.05±2.92% vs. 13.08±3.88%; p=0.01) and slow wave sleep (SWS) (stage 3 duration: 9.02±7.84% vs. 14.44±7.32%; p=0.03) than women. No differences were found between the two groups in the level of pain, emotional distress, or daily functioning. However, pain in men, fatigue in women, and functional impact in both sexes seemed to be related to worse sleep quality. Also in women, alterations in total sleep time (TST) and rapid eye movement (REM) sleep features appeared to be related to emotional status. Alterations in sleep respiratory patterns were more highly prevalent in male than in female FM patients. More so in male FM patients, the alterations in sleep patterns, non-refreshing sleep, and other FM-related symptoms observed in this population might be part of a primary sleep-disordered breathing.


Impact of a newly opened prison on an accident and emergency department.
To determine the impact of a newly opened prison on an accident and emergency (A&E) department. A new category B prison opened in April 1999, the first privately run prison in Scotland and the third largest in population. All prisoners referred to the A&E department for treatment were identified prospectively during the first year after the opening of the prison. 99 prisoners and four members of staff attended during the one year period. Ages ranged from 18-64 years with a mean age of 29.8 years. Presentations were as a result of deliberate self harm (22%), injury after violence (18%), sports injury (15%), surgical condition (15%), medical illness (13%), accidental injury (9%), ENT problem (2%), and miscellaneous (6%). Thirty seven prisoners (35.6%) were admitted to the hospital. Further review at outpatient clinics was arranged for 15 prisoners. One prisoner died, the result of suicide by hanging. The remaining prisoners were returned to the prison for further management by the prison medical and nursing team. Twelve prisoners re-attended a total of 37 times, ranging from twice to a maximum of eight visits. Some 42.3% of attendances were during "working hours" (09.00-17.00) and 57.7% attended "out of hours" (17.00-09.00). Twenty four referrals (23.1%) were deemed inappropriate by the prison medical team on retrospective review. Sixteen of these occurred "out of hours". Forty one prisoners (39.4%) were known to have a history of injecting drug misuse. Including re-attenders, 59 presentations (56.7%) to the A&E department had a history of injecting drug misuse. Of these 41 prisoners, 11 (26.8%) were hepatitis C positive, with eight of these having a positive polymerase chain reaction test. No prisoners had HIV and only one prisoner was hepatitis B positive. The opening of the prison resulted in only a slight increase in the workload of the A&E department. A significant proportion of prisoners were admitted to the hospital highlighting the practical and logistical problems of managing people restrained and in custody. Most cases can be safely referred back to the prison. Increased input is required from the prison medical team when dealing with deliberate self harm, frequent attenders, and "out of hours" referrals. All A&E staff must be aware of the increased risk of hepatitis C infection when dealing with a confined prison population.


Freshwater Fossil Pearls from the Nihewan Basin, Early Early Pleistocene.
Fossil blister pearls attached to the shells of an Anodonta mollusk from China, early Early Pleistocene, are reported here for the first time. The pearls were investigated in detail using a variety of methods. Micro-CT scanning of the fossil pearls was carried out to discover the inner structure and the pearl nucleus. Using CTAn software, changes in the gray levels of the biggest pearl, which reflect the changing density of the material, were investigated. The results provide us with some clues on how these pearls were formed. Sand grains, shell debris or material with a similar density could have stimulated the development of these pearls. X-ray diffraction analysis of one fossil pearl and the shell to which it was attached reveals that only aragonite exists in both samples. The internal structures of our fossil shells and pearls were investigated using a Scanning Electron Microscope. These investigations throw some light on pearl development in the past.


Olfactory impairment and subjective olfactory complaints independently predict conversion to dementia: a longitudinal, population-based study.
We examined whether conversion to dementia can be predicted by self-reported olfactory impairment and/or by an inability to identify odors. Common forms of dementia involve an impaired sense of smell, and poor olfactory performance predicts cognitive decline among the elderly. We followed a sample of 1529 participants, who were within a normal range of overall cognitive function at baseline, over a 10-year period during which 159 were classified as having a dementia disorder. Dementia conversion was predicted from demographic variables, Mini-Mental State Examination score, and olfactory assessments. Self-reported olfactory impairment emerged as an independent predictor of dementia. After adjusting for effects of other predictors, individuals who rated their olfactory sensitivity as "worse than normal" were more likely to convert to dementia than those who reported normal olfactory sensitivity (odds ratio [OR] = 2.17; 95% confidence interval [CI] [1.40, 3.37]). Additionally, low scores on an odor identification test also predicted conversion to dementia (OR per 1 point increase = 0.89; 95% CI [0.81, 0.98]), but these two effects were additive. We suggest that assessing subjective olfactory complaints might supplement other assessments when evaluating the risk of conversion to dementia. Future studies should investigate which combination of olfactory assessments is most useful in predicting dementia conversion.


Urotensin-II receptor ligands. From agonist to antagonist activity.
Urotensin II (U-II) is a disulfide bridged peptide hormone recently identified as the ligand of a G-protein-coupled receptor. Human U-II (H-Glu-Thr-Pro-Asp-cyclo[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) has been described as the most potent vasoconstrictor compound identified to date. We have recently identified both a superagonist of hU-II termed P5U and the compound termed urantide, which is the most potent UT receptor peptide antagonist described to date. Our previous conformational studies showed that hU-II and its analogues with agonist activity adopt a well-defined type II' beta-hairpin structure in anisotropic SDS membrane-like environment. This structural arrangement allows tight contact among the Trp7, Lys8, and Tyr9 side chains, which is fundamental to obtain full agonist activity. Here, we report an extensive SAR study on new analogues with agonist/antagonist activity on UT receptor. We investigated their biological activity and performed a conformational analysis by spectroscopic and computational methods. Our goal is to obtain a structure-based model able to explain the agonist/antagonist functional switching of these ligands.


Phase unwrapping through demodulation by use of the regularized phase-tracking technique.
Most interferogram demodulation techniques give the detected phase wrapped owing to the arctangent function involved in the final step of the demodulation process. To obtain a continuous detected phase, an unwrapping process must be performed. Here we propose a phase-unwrapping technique based on a regularized phase-tracking (RPT) system. Phase unwrapping is achieved in two steps. First, we obtain two phase-shifted fringe patterns from the demodulated wrapped phase (the sine and the cosine), then demodulate them by using the RPT technique. In the RPT technique the unwrapping process is achieved simultaneously with the demodulation process so that the final goal of unwrapping is therefore achieved. The RPT method for unwrapping the phase is compared with the technique of least-squares integration of wrapped phase differences to outline the substantial noise robustness of the RPT technique.


Hypolipidemic Effect of Tomato Juice in Hamsters in High Cholesterol Diet-Induced Hyperlipidemia.
Tomato is a globally famous food and contains several phytonutrients including lycopene, β-carotene, anthocyanin, and flavonoids. The increased temperature used to produce tomato juice, ketchup, tomato paste and canned tomato enhances the bioactive composition. We aimed to verify the beneficial effects of processed tomato juice from Kagome Ltd. (KOT) on hypolipidemic action in hamsters with hyperlipidemia induced by a 0.2% cholesterol and 10% lard diet (i.e., high-cholesterol diet (HCD)). Male Golden Syrian hamsters were randomly divided into two groups for treatment: normal (n = 8), standard diet (control); and experimental (n = 32), HCD. The 32 hamsters were further divided into four groups (n = 8 per group) to receive vehicle or KOT by oral gavage at 2787, 5573, or 13,934 mg/kg/day for six weeks, designated the HCD-1X, -2X and -5X groups, respectively. The efficacy and safety of KOT supplementation was evaluated by lipid profiles of serum, liver and feces and by clinical biochemistry and histopathology. HCD significantly increased serum levels of total cholesterol (TC), triacylglycerol (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), LDL-C/HDL-C ratio, hepatic and fetal TC and TG levels, and degree of fatty liver as compared with controls. KOT supplementation dose-dependently decreased serum TC, TG, LDL-C levels, LDL-C/HDL-C ratio, hepatic TC and TG levels, and fecal TG level. Our study provides experiment-based evidence to support that KOT may be useful in treating or preventing the onset of hyperlipidemia.


A novel mechanism controlling resetting speed of the circadian clock to environmental stimuli.
Many aspects of mammalian physiology are driven through the coordinated action of internal circadian clocks. Clock speed (period) and phase (temporal alignment) are fundamental to an organism's ability to synchronize with its environment. In humans, lifestyles that disturb these clocks, such as shift work, increase the incidence of diseases such as cancer and diabetes. Casein kinases 1δ and ε are closely related clock components implicated in period determination. However, CK1δ is so dominant in this regard that it remains unclear what function CK1ε normally serves. Here, we reveal that CK1ε dictates how rapidly the clock is reset by environmental stimuli. Genetic disruption of CK1ε in mice enhances phase resetting of behavioral rhythms to acute light pulses and shifts in light cycle. This impact of CK1ε targeting is recapitulated in isolated brain suprachiasmatic nucleus and peripheral (lung) clocks during NMDA- or temperature-induced phase shift in association with altered PERIOD (PER) protein dynamics. Importantly, accelerated re-entrainment of the circadian system in vivo and in vitro can be achieved in wild-type animals through pharmacological inhibition of CK1ε. These studies therefore reveal a role for CK1ε in stabilizing the circadian clock against phase shift and highlight it as a novel target for minimizing physiological disturbance in shift workers.


Primaquine for prevention of malaria in travelers.
An expanding risk and range of endemic malaria threatens travelers. Primaquine is an old drug recently demonstrated to offer effective prophylaxis. Clinical trials conducted in Indonesia, Kenya, and Colombia showed that a primaquine base (30 mg per day) had protective efficacy against Plasmodium falciparum and Plasmodium vivax of 85%-93%. Among 339 children (age, >8 years) and adults taking this regimen for 12-52 weeks, there was no greater risk of adverse symptomatic events among primaquine users than among recipients of placebo in double-blind studies. Among 151 subjects evaluated after 20 or 52 weeks of daily primaquine therapy, methemoglobinemia was found to be mild (<13%; typically <6%) and transient (duration, <2 weeks). We consider primaquine base (0.5 mg/kg per day consumed with food) to be safe, well-tolerated, and effective prophylaxis against malaria for nonpregnant persons and those with normal glucose-6-phosphate dehydrogenase levels. Primaquine's major advantage over most drugs for chemoprophylaxis is that it does not have to be taken before entering or beyond 3 days after leaving a malarious area.


Electrocardiographic abnormalities among people with HIV in Shanghai, China.
People living with HIV (PLWH) have an excess risk of cardiovascular diseases (CVD). Electrocardiographic (ECG) abnormalities are independently predictive of incident cardiovascular events in the general population. Our study aimed to evaluate the prevalence and correlates of ECG abnormalities among PLWH in Shanghai, China. We used a cross-sectional design to collect data from Shanghai Public Health Clinical Center, China. A total of 587 HIV-infected patients aged between 18 and 75 years were recruited between January 2015 and February 2016. The overall prevalence of any type of ECG abnormalities was 53.3%. The prevalence of sinus tachycardia, ST-T segment elevation and left ventricular hypertrophy was 23.0%, 18.1%, and 6.8%, respectively. Multivariable logistic regression analysis indicated that ST-T segment elevation was positively associated with higher baseline HIV viral load (≥ 4 log10 copies/mL), and sinus tachycardia was negatively associated with older age but positively associated with lower CD4 cell count, higher baseline HIV viral load (≥ 4 log10 copies/mL) and higher lactic dehydrogenase (LDH) level (≥133 mg/dL). Any coded ECG abnormality was positively associated with higher baseline HIV viral load (≥ 4 log10 copies/mL). ECG abnormalities including sinus tachycardia and ST-T segment elevation are prevalent among Chinese HIV patients, which are significantly associated with immunodeficiency and HIV viral load. Routine ECG screening may be an important part of HIV clinical care in China.


Influence of duration of phosphoric acid pre-etching on bond durability of universal adhesives and surface free-energy characteristics of enamel.
The purpose of this study was to evaluate the influence of duration of phosphoric acid pre-etching on the bond durability of universal adhesives and the surface free-energy characteristics of enamel. Three universal adhesives and extracted human molars were used. Two no-pre-etching groups were prepared: ground enamel; and enamel after ultrasonic cleaning with distilled water for 30 s to remove the smear layer. Four pre-etching groups were prepared: enamel pre-etched with phosphoric acid for 3, 5, 10, and 15 s. Shear bond strength (SBS) values of universal adhesive after no thermal cycling and after 30,000 or 60,000 thermal cycles, and surface free-energy values of enamel surfaces, calculated from contact angle measurements, were determined. The specimens that had been pre-etched showed significantly higher SBS and surface free-energy values than the specimens that had not been pre-etched, regardless of the aging condition and adhesive type. The SBS and surface free-energy values did not increase for pre-etching times of longer than 3 s. There were no significant differences in SBS values and surface free-energy characteristics between the specimens with and without a smear layer. The results of this study suggest that phosphoric acid pre-etching of enamel improves the bond durability of universal adhesives and the surface free-energy characteristics of enamel, but these bonding properties do not increase for phosphoric acid pre-etching times of longer than 3 s.


Challenges to successful implementation of HIV and AIDS-related health policies in Cartagena, Colombia.
The Caribbean region presents the highest prevalence of HIV/AIDS worldwide after sub-Saharan Africa; leading to serious social, economic and health consequences at the local scale but also at the regional and global levels. In Colombia, a national plan to tackle the epidemic was formulated with little evidence that its implementation in the local context is effective. This study focused on Cartagena - one of Colombia's largest cities and an international touristic hub - that presents one of the highest HIV prevalences in the country, to investigate whether the national plan accounts for local specificities and what are the barriers to local implementation. Based on the Contextual Interaction Theory (CIT), this qualitative research relied upon 27 interviews and 13 life stories of local inhabitants and stakeholders, collected in a first fieldwork in 2006-2007. A follow-up data collection took place in 2013 with 10 participants: key policymakers and implementers, NGO representatives and local inhabitants. Barriers identified by the participants included: local population's understandings and beliefs on condom use; stigma and discrimination; lack of collaboration from the Church, the education sector and local politicians; corruption; high staff turnover; frequent changes in leadership; lack of economic and human resources; and barriers to health care access. The findings suggest that global influences also have an impact on the CIT framework (e.g. international organisations as a major financier in HIV prevention). The participants put forward several feasible solutions to implementation barriers. We discuss how several of the proposed solutions have been applied in other Latin American and Caribbean countries and yielded positive results. However, further research is needed to find possible ways of overcoming certain barriers identified by this study such as corruption, the lack of collaboration of the Church and barriers to health care access.


The complex remuneration of human resources for health in low-income settings: policy implications and a research agenda for designing effective financial incentives.
Human resources for health represent an essential component of health systems and play a key role to accelerate progress towards universal health coverage. Many countries in sub-Saharan Africa face challenges regarding the availability, distribution and performance of health workers, which could be in part addressed by providing effective financial incentives. Based on an overview of the existing literature, the paper highlights the gaps in the existing research in low-income countries exploring the different components of health workers' incomes. It then proposes a novel approach to the analysis of financial incentives and delineates a research agenda, which could contribute to shed light on this topic. The article finds that, while there is ample research that investigates separately each of the incomes health workers may earn (for example, salary, fee-for-service payments, informal incomes, "top-ups" and per diems, dual practice and non-health activities), there is a dearth of studies which look at the health workers' "complex remuneration", that is, the whole of the financial incentives available. Little research exists which analyses simultaneously all revenues of health workers, quantifies the overall remuneration and explores its complexity, its multiple components and their features, as well as the possible interaction between income components. However, such a comprehensive approach is essential to fully comprehend health workers' incentives, by investigating the causes (at individual and system level) of the fragmentation in the income structure and the variability in income levels, as well as the consequences of the "complex remuneration" on motivation and performance. This proposition has important policy implications in terms of devising effective incentive packages as it calls for an active consideration of the role that "complex remuneration" plays in determining recruitment, retention and motivation patterns, as well as, more broadly, the performance of health systems. This paper argues that research focusing on the health workers' "complex remuneration" is critical to address some of the most challenging issues affecting human resources for health. An empirical research agenda is proposed to fill the gap in our understanding.


Comparison between massage and music therapies to relieve the severity of labor pain.
During labor, women experience a high level of intense, stressful and steady pain that may negatively affect both mothers and neonates. Painkillers have previously been used for childbearing women, but nowadays, owing to some well-known limitations and serious side effects, nonpharmacologic methods such as massage and music therapies are being broadly recommended. The present clinical trial was conducted to compare the effects of massage and music therapies on the severity of labor pain in the Ilam province of western Iran. Overall, 101 primigravidae who were hospitalized for vaginal delivery were recruited and randomly stratified into two groups of either massage (n = 51) or music (n = 50) therapies. Pain was measured using the visual analog scale and the two groups were compared in terms of pain severity before and after the interventions. Mothers in the massage therapy group had a lower level of pain compared with those in the music therapy group (p = 0.009). A significant difference was observed between the two groups in terms of pain severity after intervention (p = 0.01). Agonizing, or most severe, labor pain was significantly relieved after massage therapy (p = 0.001). Massage therapy was an effective method for reducing and relieving labor pain compared with music therapy and can be clinically recommended as an alternative, safe and affordable method of pain relief where using either pharmacological or nonpharmacological methods are optional.


Trends in the use of implantable accelerated partial breast irradiation therapy for early stage breast cancer in the United States.
In 2002, the US Food and Drug Administration approved an implantable balloon catheter that delivers accelerated partial breast irradiation (APBI) after breast-conserving surgery (BCS). The objective of the current study was to determine the use of implantable APBI (IAPBI) in the United States and factors associated with IAPBI use. By using the Surveillance, Epidemiology, and End Results database, the authors conducted a retrospective analysis of patients who received whole-breast radiotherapy (WBRT) or IAPBI after BCS for ductal carcinoma in situ, AJCC stage I, or stage II breast cancer from 2000 to 2007. WBRT and IAPBI rates were determined across time and demographic and tumor factors using chi-square tests and Cochran-Armitage tests for trend for the unadjusted analyses. A total of 127,257 patients who met inclusion criteria were identified. Over the study period, the proportion of patients receiving IAPBI increased by 1600% (from 0.4% in 2000 to 6.8% in 2007; P <.001). This trend remained significant when using logistic regression (odds ratio, 20.3; 95% confidence interval, 15.5-26.6). The increase in IAPBI use was statistically significant across all stage and age categories >40 years (P <.001). The use of IAPBI was most notable in older women (ages 70-79 years), with a >2100% increase in use noted during the study period (0.4% in 2000 vs 9.0% in 2007; P <.001). The authors also found significant variation in IAPBI use by region. IAPBI use has markedly increased since 2000, particularly in the elderly population. The rapid and widespread adoption of IAPBI is concerning, because large multicenter randomized controlled trials have not yet demonstrated the long-term effectiveness of IAPBI compared with WBRT.


Diffusive and Arrestedlike Dynamics in Currency Exchange Markets.
This work studies the symmetry between colloidal dynamics and the dynamics of the Euro-U.S. dollar currency exchange market (EURUSD). We consider the EURUSD price in the time range between 2001 and 2015, where we find significant qualitative symmetry between fluctuation distributions from this market and the ones belonging to colloidal particles in supercooled or arrested states. In particular, we find that models used for arrested physical systems are suitable for describing the EURUSD fluctuation distributions. Whereas the corresponding mean-squared price displacement (MSPD) to the EURUSD is diffusive for all years, when focusing in selected time frames within a day, we find a two-step MSPD when the New York Stock Exchange market closes, comparable to the dynamics in supercooled systems. This is corroborated by looking at the price correlation functions and non-Gaussian parameters and can be described by the theoretical model. We discuss the origin and implications of this analogy.


Astaxanthin reduces type 2 diabetic‑associated cognitive decline in rats via activation of PI3K/Akt and attenuation of oxidative stress.
Astaxanthin (AST) is an oxygenated derivative of carotenoid, which possesses a strong antioxidant activity. AST can effectively remove active oxygen from the body, and is thus considered to have an important role in disease prevention and treatment. The present study aimed to determine the effects of AST on type 2 diabetic‑associated cognitive decline (DACD) in rats. Rats were intraperitoneally injected with streptozotocin (STZ), in order to establish a model of diabetes mellitus (DM). A total of 40 rats were randomly divided into five groups: The control group, the DM group, the AST (50 mg/kg) group, the AST (100 mg/kg) group, and the AST+LY294002 group (AST, 50 mg/kg and LY, 0.25 µg/100 g). Following a 14‑day treatment with AST, the body weight, blood glucose levels and cognitive function were determined. In addition, the protein expression levels of phosphatidylinositol 3‑kinase (PI3K)/Akt, glutathione peroxidase and superoxide dismutase activity, glutathione and malondialdehyde content, and inducible nitric oxide synthase (iNOS), caspase‑3 and caspase‑9 activity were detected in the rats with DM. AST clearly augmented body weight and reduced blood glucose levels in rats with DM. Furthermore, treatment with AST significantly improved the cognitive function of rats with DM. Treatment with AST activated the PI3K/Akt pathway, and suppressed oxidative stress in the DM rats. In the cerebral cortex and hippocampus of the rats with DM, the activities of iNOS, caspase‑3 and caspase‑9 were markedly reduced. Furthermore, treatment with the Akt inhibitor LY294002 reduced the effectiveness of AST on DACD in rats. In conclusion, AST may reduce type 2 DACD in rats via activation of PI3K/Akt and attenuation of oxidative stress.


Delusional Ideation, Cognitive Processes and Crime Based Reasoning.
Probabilistic reasoning biases have been widely associated with levels of delusional belief ideation (Galbraith, Manktelow, & Morris, 2010; Lincoln, Ziegler, Mehl, & Rief, 2010; Speechley, Whitman, & Woodward, 2010; White & Mansell, 2009), however, little research has focused on biases occurring during every day reasoning (Galbraith, Manktelow, & Morris, 2011), and moral and crime based reasoning (Wilkinson, Caulfield, & Jones, 2014; Wilkinson, Jones, & Caulfield, 2011). 235 participants were recruited across four experiments exploring crime based reasoning through different modalities and dual processing tasks. Study one explored delusional ideation when completing a visually presented crime based reasoning task. Study two explored the same task in an auditory presentation. Study three utilised a dual task paradigm to explore modality and executive functioning. Study four extended this paradigm to the auditory modality. The results indicated that modality and delusional ideation have a significant effect on individuals reasoning about violent and non-violent crime (p < .05), which could have implication for the presentation of evidence in applied setting such as the courtroom.


Crustal plates in the central atlantic.
Various people have proposed that North and South America are a part of a gigantic crustal plate within which little differential movement is taking place. Considerations of the size of this postulated plate and the pattern of seismicity around the Caribbean indicate that it is in fact two plates, separated in the region between the Lesser Antilles and the Mid-Atlantic Ridge. Many of the offsets of the Mid-Atlantic Ridge opposite the Caribbean are the result of differential spreading rates and the westward continuations of the fracture zones extending from these offsets are active left-lateral faults.


Inferior parietal lobule contributions to visual word recognition.
This study investigated how the left inferior parietal lobule (IPL) contributes to visual word recognition. We used repetitive TMS to temporarily disrupt neural information processing in two anatomical fields of the IPL, namely, the angular (ANG) and supramarginal (SMG) gyri, and observed the effects on reading tasks that focused attention on either the meaning or sounds of written words. Relative to no TMS, stimulation of the left ANG selectively slowed responses in the meaning, but not sound, task, whereas stimulation of the left SMG affected responses in the sound, but not meaning, task. These results demonstrate that ANG and SMG doubly dissociate in their contributions to visual word recognition. We suggest that this functional division of labor may be understood in terms of the distinct patterns of cortico-cortical connectivity resulting in separable functional circuits.


Effect of acute copper exposure on gastrointestinal permeability in healthy volunteers.
In vitro studies indicate that treating cells with copper results in alteration of tight junction permeability. In humans, ingestion of a single bolus of up to 10 mg Cu/L (as copper sulfate) causes nausea and vomiting in approximately 20 and 5% of the volunteers, respectively. To understand better the gastric and intestinal effects of copper, in this study we evaluated in asymptomatic volunteers (1) the effects of acute copper ingestion on gastric and intestinal permeability and (2) whether the appearance of gastrointestinal symptoms is associated with changes in mucosal permeability. Thirty-one asymptomatic subjects were assessed in a randomized, double-blind, crossover study that included two permeability tests, one after ingesting 200 ml distilled water and the other after ingesting 200 ml water containing 10 mg Cu/L (as copper sulfate). Fifteen minutes after ingestion subjects drank a second solution containing 40 g sucrose, 7.5 g lactulose, and 2 g mannitol, and urine was collected for 5 hr. Sugar concentrations were determined by gas chromatography. Symptoms during the trials were recorded in self-administered questionnaires. Ingestion of the 10 mg/L copper solution significantly increased gastric permeability to sucrose [20.8 (11.8-73.4) vs 28.4 (16.6-113.9) mg, respectively; P = 0.0064] but did not change intestinal permeability to lactulose/mannitol [0.87 (0.53-2.06) vs 1.17 (0.58-2.39)%, respectively; P = 0.18]. Gastrointestinal symptoms were reported during both the basal and the experimental conditions, but after copper ingestion they increased to 22.6% of the subjects and were significantly more intense than under basal conditions (P = 0.047). However, changes in permeability were not related to the appearance of symptoms. These results indicate that acute oral exposure to 10 mg Cu/L exerts an effect on gastric but not intestinal mucosa, reducing the gastric mucosal barrier capacity, independently of the appearance of gastrointestinal symptoms.


Assessing exertional dyspnea in patients with idiopathic pulmonary fibrosis.
Dyspnea is a hallmark symptom of idiopathic pulmonary fibrosis (IPF), and dyspnea induced physical activity limitation is a prominent driver of quality of life impairment among IPF patients. We examined response data for the 21 physical activity items (the first 21 of 24) from the University of California San Diego Shortness of Breath Questionnaire (UCSD) collected at baseline in a recently conducted IPF trial. We used Rasch analysis and hypothesis testing with conventional statistical methodology to achieve three objectives: 1) to examine the items to identify the one characteristic that distinguishes one from another; 2) to asses these items for their ability to measure dyspnea severity in IPF; 3) to use the items to develop a dyspnea ruler. The sample comprised 178 subjects. The 21 items fit the Rasch model. There was very strong correlation between Rasch item severity and their metabolic equivalents (METS) values (r = -0.86, p < 0.0001). With the sample stratified on scores from the 21 items, there were significant between group differences in FVC%, DLCO% and distance walked during the six-minute walk test. The dyspnea ruler can be used to put dyspnea levels in a more easily understood clinical context. The first 21 items from the UCSD compose a unidimensional dyspnea-with-activity scale and are both sensibly ordered and distinguished from each other by their METS values. These 21 items can be used confidently to formulate clinically-relevant inferences about IPF patients and should be considered for use as a meaningful endpoint in IPF research.


CsrA regulates glycogen biosynthesis by preventing translation of glgC in Escherichia coli.
The carbon storage regulatory system of Escherichia coli controls the expression of genes involved in carbohydrate metabolism and cell motility. CsrA binding to glgCAP transcripts inhibits glycogen metabolism by promoting glgCAP mRNA decay. CsrB RNA functions as an antagonist of CsrA by sequestering this protein and preventing its action. In this paper, we elucidate further the mechanism of CsrA-mediated glgC regulation. Results from gel shift assays demonstrate that several molecules of CsrA can bind to each glgC transcript. RNA footprinting studies indicate that CsrA binds to the glgCAP leader transcript at two positions. One of these sites overlaps the glgC Shine-Dalgarno sequence, whereas the other CsrA target is located further upstream in an RNA hairpin. Results from toeprint and cell-free translation experiments indicate that bound CsrA prevents ribosome binding to the glgC Shine-Dalgarno sequence and that this reduces GlgC synthesis. The effect of two deletions in the upstream binding site was examined. Both of these deletions reduced, but did not eliminate, CsrA binding in vitro and CsrA-dependent regulation in vivo. Our findings establish that bound CsrA inhibits initiation of glgC translation, thereby reducing glycogen biosynthesis. This inhibition of translation probably contributes to destabilization of the glgC transcript that was observed previously.


Simulating an emergency department: the importance of modeling the interactions between physicians and delegates in a discrete event simulation.
Computer simulation studies of the emergency department (ED) are often patient driven and consider the physician as a human resource whose primary activity is interacting directly with the patient. In many EDs, physicians supervise delegates such as residents, physician assistants and nurse practitioners each with different skill sets and levels of independence. The purpose of this study is to present an alternative approach where physicians and their delegates in the ED are modeled as interacting pseudo-agents in a discrete event simulation (DES) and to compare it with the traditional approach ignoring such interactions. The new approach models a hierarchy of heterogeneous interacting pseudo-agents in a DES, where pseudo-agents are entities with embedded decision logic. The pseudo-agents represent a physician and delegate, where the physician plays a senior role to the delegate (i.e. treats high acuity patients and acts as a consult for the delegate). A simple model without the complexity of the ED is first created in order to validate the building blocks (programming) used to create the pseudo-agents and their interaction (i.e. consultation). Following validation, the new approach is implemented in an ED model using data from an Ontario hospital. Outputs from this model are compared with outputs from the ED model without the interacting pseudo-agents. They are compared based on physician and delegate utilization, patient waiting time for treatment, and average length of stay. Additionally, we conduct sensitivity analyses on key parameters in the model. In the hospital ED model, comparisons between the approach with interaction and without showed physician utilization increase from 23% to 41% and delegate utilization increase from 56% to 71%. Results show statistically significant mean time differences for low acuity patients between models. Interaction time between physician and delegate results in increased ED length of stay and longer waits for beds. This example shows the importance of accurately modeling physician relationships and the roles in which they treat patients. Neglecting these relationships could lead to inefficient resource allocation due to inaccurate estimates of physician and delegate time spent on patient related activities and length of stay.