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

The formation of organizational reputation

In this article, we review four decades of research on the formation of organizational reputation. Our review reveals six perspectives that have informed past studies: a game theoretic, a strategic, a macro-cognitive, a micro-cognitive, a cultural-sociological, and communicative one. We compare and contrast the different assumptions about what reputation is and how it forms that characterize these perspectives, and we discuss the implications of these differences for our theoretical understanding of stability and change, control and contestation, and the micro-macro relationship in the complex process of reputation formation

Differential gaze behavior towards sexually preferred and non-preferred human figures

The gaze pattern associated with image exploration is a sensitive index of our attention, motivation and preference. To examine whether an individual’s gaze behavior can reflect his/her sexual interest, we compared gaze patterns of young heterosexual men and women (M = 19.94 years, SD = 1.05) while viewing photos of plain-clothed male and female figures aged from birth to sixty years old. Our analysis revealed a clear gender difference in viewing sexually preferred figure images. Men displayed a distinctive gaze pattern only when viewing twenty-year-old female images, with more fixations and longer viewing time dedicated to the upper body and waist-hip region. Women also directed more attention at the upper body on female images in comparison to male images, but this difference was not age-specific. Analysis of local image salience revealed that observers’ eye-scanning strategies could not be accounted for by low-level processes, such as analyzing local image contrast and structure, but were associated with attractiveness judgments. The results suggest that the difference in cognitive processing of sexually preferred and non-preferred figures can be manifested in gaze patterns associated with figure viewing. Thus, eye-tracking holds promise as a potential sensitive measure for sexual preference, particularly in men

Stimulus- and Neural-Referred Visual Receptive Field Properties following Hemispherectomy:A Case Study Revisited

Contains fulltext : 208072.pdf (publisher's version ) (Open Access

Quantized spin wave modes in magnetic tunnel junction nanopillars

We present an experimental and theoretical study of the magnetic field dependence of the mode frequency of thermally excited spin waves in rectangular shaped nanopillars of lateral sizes 60x100, 75x150, and 105x190 nm2, patterned from MgO-based magnetic tunnel junctions. The spin wave frequencies were measured using spectrally resolved electrical noise measurements. In all spectra, several independent quantized spin wave modes have been observed and could be identified as eigenexcitations of the free layer and of the synthetic antiferromagnet of the junction. Using a theoretical approach based on the diagonalization of the dynamical matrix of a system of three coupled, spatially confined magnetic layers, we have modeled the spectra for the smallest pillar and have extracted its material parameters. The magnetization and exchange stiffness constant of the CoFeB free layer are thereby found to be substantially reduced compared to the corresponding thin film values. Moreover, we could infer that the pinning of the magnetization at the lateral boundaries must be weak. Finally, the interlayer dipolar coupling between the free layer and the synthetic antiferromagnet causes mode anticrossings with gap openings up to 2 GHz. At low fields and in the larger pillars, there is clear evidence for strong non-uniformities of the layer magnetizations. In particular, at zero field the lowest mode is not the fundamental mode, but a mode most likely localized near the layer edges.Comment: 16 pages, 4 figures, (re)submitted to PR

Multiple evolutionary trajectories have led to the emergence of races in <em>Fusarium oxysporum</em> f. sp. <em>lycopersici</em>

Race 1 isolates of Fusarium oxysporum f. sp. lycopersici (FOL) are characterized by the presence of AVR1 in their genomes. The product of this gene, Avr1, triggers resistance in tomato cultivars carrying resistance gene I. In FOL race 2 and race 3 isolates, AVR1 is absent, and hence they are virulent on tomato cultivars carrying I. In this study, we analyzed an approximately 100-kb genomic fragment containing the AVR1 locus of FOL race 1 isolate 004 (FOL004) and compared it to the sequenced genome of FOL race 2 isolate 4287 (FOL4287). A genomic fragment of 31 kb containing AVR1 was found to be missing in FOL4287. Further analysis suggests that race 2 evolved from race 1 by deletion of this 31-kb fragment due to a recombination event between two transposable elements bordering the fragment. A worldwide collection of 71 FOL isolates representing races 1, 2, and 3, all known vegetative compatibility groups (VCGs), and five continents was subjected to PCR analysis of the AVR1 locus, including the two bordering transposable elements. Based on phylogenetic analysis using the EF1-α gene, five evolutionary lineages for FOL that correlate well with VCGs were identified. More importantly, we show that FOL races evolved in a stepwise manner within each VCG by the loss of function of avirulence genes in a number of alternative ways. IMPORTANCE Plant-pathogenic microorganisms frequently mutate to overcome disease resistance genes that have been introduced in crops. For the fungus Fusarium oxysporum f. sp. lycopersici, the causal agent of Fusarium wilt in tomato, we have identified the nature of the mutations that have led to the overcoming of the I and I-2 resistance genes in all five known clonal lineages, which include a newly discovered lineage. Five different deletion events, at least several of which are caused by recombination between transposable elements, have led to loss of AVR1 and overcoming of I. Two new events affecting AVR2 that led to overcoming of I-2 have been identified. We propose a reconstruction of the evolution of races in FOL, in which the same mutations in AVR2 and AVR3 have occurred in different lineages and the FOL pathogenicity chromosome has been transferred to new lineages several times

Preserved retinotopic brain connectivity in macular degeneration

PURPOSE: The eye disease macular degeneration (MD) is a leading cause of blindness worldwide. There is no cure for MD, but several promising treatments aimed at restoring vision at the level of the retina are currently under investigation. These treatments assume that the patient's brain can still process appropriately the retinal input once it is restored, but whether this assumption is correct has yet to be determined. METHODS: We used functional magnetic resonance imaging (fMRI) and connective field modelling to determine whether the functional connectivity between the input-deprived portions of primary visual cortex (V1) and early extrastriate areas (V2/3) is still retinotopically organised. Specifically, in both patients with juvenile macular degeneration and age-matched controls with simulated retinal lesions, we assessed the extent to which the V1-referred connective fields of extrastriate voxels, as estimated on the basis of spontaneous fMRI signal fluctuations, adhered to retinotopic organisation. RESULTS: We found that functional connectivity between the input-deprived portions of visual areas V1 and extrastriate cortex is still largely retinotopically organised in MD, although on average less so than in controls. Patients with stable fixation exhibited normal retinotopic connectivity, however, suggesting that for the patients with unstable fixation, eye-movements resulted in spurious, homogeneous signal modulations across the entire input-deprived cortex, which would have hampered our ability to assess their spatial structure of connectivity. CONCLUSIONS: Despite the prolonged loss of visual input due to MD, the cortico-cortical connections of input-deprived visual cortex remain largely intact. This suggests that the restoration of sight in macular degeneration can rely on a largely unchanged retinotopic representation in early visual cortex following loss of central retinal function