Pharmacokinetics and pharmacodynamics of tiotropium solution and tiotropium powder in chronic obstructive pulmonary disease

The aim of the study was to characterize pharmacokinetics of tiotropium solution 5 µg compared to powder 18 µg and assess dose-dependency of tiotropium solution pharmacodynamics in comparison to placebo. In total 154 patients with chronic obstructive pulmonary disease (COPD) were included in this multicenter, randomized, double-blind within-solution (1.25, 2.5, 5 µg, and placebo), and open-label powder 18 µg, crossover study, including 4-week treatment periods. Primary end points were peak plasma concentration (Cmax,ss ), and area under the plasma concentration-time profile (AUC0-6h,ss ), both at steady state. The pharmacodynamic response was assessed by serial spirometry (forced expiratory volume in 1 second/forced vital capacity). Safety was evaluated as adverse events and by electrocardiogram/Holter. Tiotropium was rapidly absorbed with a median tmax,ss of 5-7 minutes postdosing for both devices. The gMean ratio of solution 5 µg over powder 18 µg was 81% (90% confidence interval, 73-89%) for Cmax,ss and 76% (70-82%) for AUC0-6h,ss , indicating that bioequivalence was not established. Dose ordering for bronchodilation was observed. Powder 18 µg and solution 5 µg were most effective, providing comparable bronchodilation. All treatments were well tolerated with no apparent relation to dose or device. Comparable bronchodilator efficacy to powder18 µg at lower systemic exposure supports tiotropium solution 5 µg for maintenance treatment of COPD

Ground and space based optical analysis of materials degradation in low-Earth-orbit

There is strong interest in being able to accurately and sensitively monitor materials degradation in both ground-based and space-based environments. Two optical techniques for sensitive degradation monitoring are reviewed: spectroscopic ellipsometry and photothermal spectroscopy. These techniques complement each other in that ellipsometry is sensitive to atomically thin surface and subsurface changes, and photothermal spectroscopy is sensitive to local defects, pin-holes, subsurface defects, and delamination. Progress in applying these spectroscopies (both ex situ and in situ) to atomic oxygen degradation of space materials is reviewed

A humanisation approach for the management of Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome-Hypermobility Type (JHS/EDS-HT).

Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome-Hypermobility Type (JHS/EDS-HT) is a complex and multisystemic condition which significantly impacts on a person's health and well-being and is challenging for health professionals (HPs) to manage. People with JHS/EDS-HT and HPs recognise the individual nature and the complexities of the condition. There is a requirement to understand the condition within the context of the individual human dimensions of illness and healing. The aim of this paper is to explore the management of this condition using a theoretical model referred to as the Humanisation Framework.  It is suggested that using the philosophical dimensions of this framework will empower HPs and those with JHS/EDS-HT to work together to proactively manage this condition. The eight dimensions of the Humanisation Framework facilitate an experiential understanding of the person within their context and environment, providing a constructive adjunct to the evidence-based management of those with JHS/EDS-HT. The humanisation framework was developed for health and social care and uses the philosophy behind well-being and what makes well-being possible. This paper explores how HPs may use aspects of the framework to understand the condition and empower and motivate those with JHS/EDS-HT to be active participants in their own well-being

Flows of people in villages and large centres in Bronze Age Italy through strontium and oxygen isotopes

This study investigates to what extent Bronze Age societies in Northern Italy were permeable accepting and integrating non-local individuals, as well as importing a wide range of raw materials, commodities, and ideas from networks spanning continental Europe and the Mediterranean. During the second millennium BC, the communities of Northern Italy engaged in a progressive stabilization of settlements, culminating in the large polities of the end of the Middle/beginning of the Late Bronze Age pivoted around large defended centres (the Terramare). Although a wide range of exotic archaeological materials indicates that the inhabitants of the Po plain increasingly took part in the networks of Continental European and the Eastern Mediterranean, we should not overlook the fact that the dynamics of interaction were also extremely active on local and regional levels. Mobility patterns have been explored for three key-sites, spanning the Early to Late Bronze Age (1900–1100 BC), namely Sant’Eurosia, Casinalbo and Fondo Paviani, through strontium and oxygen isotope analysis on a large sample size (more than 100 individuals). The results, integrated with osteological and archaeological data, document for the first time in this area that movements of people occurred mostly within a territorial radius of 50 km, but also that larger nodes in the settlement system (such as Fondo Paviani) included individuals from more distant areas. This suggests that, from a demographic perspective, the process towards a more complex socio-political system in Bronze Age Northern Italy was triggered by a largely, but not completely, internal process, stemming from the dynamics of intra-polity networks and local/regional power relationships

Summing Planar Diagrams by an Integrable Bootstrap

Correlation functions of matrix-valued fields are not generally known for massive renormalized field theories. We find the large-N limit of form factors of the (1+1)-dimensional sigma model with SU(N) X SU(N) symmetry. These form factors give a correction to the free-field approximation for the N=infinity Wightman function. The method is a combination of the 1/N-expansion of the S-matrix and Smirnov's form-factor axioms. We expand the renormalized field in terms of a free massive Bosonic field as N goes to infinity.Comment: 10 pages, revtex. Fixing of further misprints. Version to appear in Phys. Rev.

Trends in referrals to liaison psychiatry teams from UK emergency departments for patients over 65

INTRODUCTION: The number of people over the age of 65 attending Emergency Departments (ED) in the United Kingdom (UK) is increasing. Those who attend with a mental health related problem may be referred to liaison psychiatry for assessment. Improving responsiveness and integration of liaison psychiatry in general hospital settings is a national priority. To do this psychiatry teams must be adequately resourced and organised. However, it is unknown how trends in the number and type referrals of older people to liaison psychiatry teams by EDs are changing, making this difficult. METHODS: We performed a national multi-centre retrospective service evaluation, analysing existing psychiatry referral data from EDs of people over 65. We described trends in the number, rate, age, mental health presentation, and time taken to assessment over a 7 years period. RESULTS: Referral data from 28 EDs across England and Scotland were analysed (n = 18,828 referrals). There was a general trend towards increasing numbers of people referred to liaison psychiatry year on year. Variability in referral numbers between different departments, ranged from 0.1 to 24.3 per 1000 ED attendances. The most common reasons for referral were mood disorders, self-harm and suicidal ideas. The majority of referrals were assessed within 60 min, however there is variability between departments, some recording waits over 11 h. DISCUSSION: The data suggests great inter-departmental variability in referral numbers. Is not possible to establish the cause of variability. However, the data highlights the importance of asking further questions about why the differences exist, and the impact that has on patient care

Génie: literature-based gene prioritization at multi genomic scale

Biomedical literature is traditionally used as a way to inform scientists of the relevance of genes in relation to a research topic. However many genes, especially from poorly studied organisms, are not discussed in the literature. Moreover, a manual and comprehensive summarization of the literature attached to the genes of an organism is in general impossible due to the high number of genes and abstracts involved. We introduce the novel Génie algorithm that overcomes these problems by evaluating the literature attached to all genes in a genome and to their orthologs according to a selected topic. Génie showed high precision (up to 100%) and the best performance in comparison to other algorithms in most of the benchmarks, especially when high sensitivity was required. Moreover, the prioritization of zebrafish genes involved in heart development, using human and mouse orthologs, showed high enrichment in differentially expressed genes from microarray experiments. The Génie web server supports hundreds of species, millions of genes and offers novel functionalities. Common run times below a minute, even when analyzing the human genome with hundreds of thousands of literature records, allows the use of Génie in routine lab work. Availability: http://cbdm.mdc-berlin.de/tools/genie/

Prediction of tissue-specific cis-regulatory modules using Bayesian networks and regression trees

<p>Abstract</p> <p>Background</p> <p>In vertebrates, a large part of gene transcriptional regulation is operated by cis-regulatory modules. These modules are believed to be regulating much of the tissue-specificity of gene expression.</p> <p>Results</p> <p>We develop a Bayesian network approach for identifying cis-regulatory modules likely to regulate tissue-specific expression. The network integrates predicted transcription factor binding site information, transcription factor expression data, and target gene expression data. At its core is a regression tree modeling the effect of combinations of transcription factors bound to a module. A new unsupervised EM-like algorithm is developed to learn the parameters of the network, including the regression tree structure.</p> <p>Conclusion</p> <p>Our approach is shown to accurately identify known human liver and erythroid-specific modules. When applied to the prediction of tissue-specific modules in 10 different tissues, the network predicts a number of important transcription factor combinations whose concerted binding is associated to specific expression.</p

CSAP localizes to polyglutamylated microtubules and promotes proper cilia function and zebrafish development

The diverse populations of microtubule polymers in cells are functionally distinguished by different posttranslational modifications, including polyglutamylation. Polyglutamylation is enriched on subsets of microtubules including those found in the centrioles, mitotic spindle, and cilia. However, whether this modification alters intrinsic microtubule dynamics or affects extrinsic associations with specific interacting partners remains to be determined. Here we identify the microtubule-binding protein centriole and spindle–associated protein (CSAP), which colocalizes with polyglutamylated tubulin to centrioles, spindle microtubules, and cilia in human tissue culture cells. Reducing tubulin polyglutamylation prevents CSAP localization to both spindle and cilia microtubules. In zebrafish, CSAP is required for normal brain development and proper left–right asymmetry, defects that are qualitatively similar to those reported previously for depletion of polyglutamylation-conjugating enzymes. We also find that CSAP is required for proper cilia beating. Our work supports a model in which polyglutamylation can target selected microtubule-associated proteins, such as CSAP, to microtubule subpopulations, providing specific functional capabilities to these populations.National Institutes of Health (U.S.) (Grant no. GM074746)American Cancer Society. Research Scholar Grant (121776)National Institute of General Medical Sciences (U.S.) (GM088313