Acetylcholine: a novel regulator of airway smooth muscle remodelling?

Increased airway smooth muscle mass is a pathological feature that asthma and chronic obstructive pulmonary disease (COPD) have in common. This increase has gained renewed interest in view of recent developments showing that airway smooth muscle, instead of solely being a contractile partner, is capable of interacting dynamically with its environment, especially under inflammatory conditions. Airway smooth muscle cells are able to proliferate, to migrate, and to secrete chemokines, cytokines, extracellular matrix proteins and growth factors, and most importantly, to adapt to these functions by changing its phenotype from contractile to proliferative/synthetic. Conversely, switching to a (hyper)contractile phenotype may also occur. A vast number of inflammatory stimuli regulate these functions and exert their effects via excitatory G_q or G_i-coupled receptors. Since acetylcholine activates muscarinic M₂ and M₃ receptors in the airway smooth muscle cell membrane, which are coupled to G_i and G_q proteins, respectively, and since acetylcholine release may be enhanced in airway inflammation, a pathophysiological role of acetylcholine related to the above processes and exceeding contraction could be envisaged. In this review, evidence in favour of this hypothesis, based on recent data that show a role for muscarinic receptors in modulating airway smooth muscle proliferation, contractility and contractile protein expression is discussed. Based on these findings, we postulate that endogenous acetylcholine contributes to airway remodeling in asthma and COPD.     

The speed-accuracy trade-off in manual prehension: effects of movement amplitude,object size and object width on kinematic characteristics

Earlier studies have suggested that the size of an object to be grasped influences the time taken to complete a prehensile movement. However, the use of cylindrical objects in those studies confounded the effects of object size — extent orthogonal to the reach axis — and object width — extent along the reach axis. In separating these effects, the present study demonstrates that movement time is not affected by manipulation of object size, as long as the latter does not approach the maximal object size that can be grasped. Object width, on the other hand, is shown to exert a systematic influence on movement time: Smaller object widths give rise to longer movement times through a lengthening of the deceleration phase of the movement, thus reproducing the effect of target width on the kinematics of aiming movements. As in aiming, movement amplitude also affects the movement time in prehension, influencing primarily the acceleration phase (i.e. peak velocity attained). The effects of object width and movement amplitude were found to combine in a way predicted by Fitts' law, allowing a generalisation of the latter to the transport component in prehensile actions. With respect to the grasp component, both object size and object width are shown to affect peak hand aperture. Increasing object width thus lowers the spatial accuracy demands on the transport component, permitting a faster movement to emerge. At the same time, the hand opens to a larger grip in order to compensate for eventual directional errors that result. Finally, with respect to the control mode of the grasp component, it was found that peak finger closing velocity scales to distance to be covered, defined as the peak hand aperture minus object size.     

Muscarinic M3-receptors mediate cholinergic synergism of mitogenesis in airway smooth muscle

Muscarinic receptor agonists have been considered to act synergistically in combination with growth facors on airway smooth muscle growth. Characterization of the proliferative responses and of the receptor subtype(s) involved has not yet been studied. Therefore, we investigated mitogenesis induced by stimulation of muscarinic receptors, alone and in combination with stimulation by platelet-derived growth factor (PDGF). For this purpose, [(3)H]thymidine-incorporation was measured at different culture stages in bovine tracheal smooth muscle cells. Functional muscarinic M(3)-receptors, as measured by formation of inositol phosphates, were present in unpassaged cells, but were lacking in passage 2 cells. Methacholine (10 microM) by itself was not able to induce a proliferative response in both cell culture stages. However, methacholine interacted synergistically with PDGF in a dose-dependent fashion (0.1-10 microM), but only in cells having functional muscarinic M(3)-receptors. This synergism could be suppressed significantly by the selective M(3)-receptor antagonists DAU 5884 (0.1 microM) and 4-DAMP (10 nM), but not at all by the M(2)-subtype selective antagonist gallamine (10 microM). These results show that methacholine potentiates mitogenesis induced by PDGF solely through stimulation of muscarinic M(3)-receptors in bovine tracheal smooth muscle cells.     

Fatigue in children: reliability and validity of the Dutch PedsQL<Superscript>TM</Superscript> Multidimensional Fatigue Scale

Purpose  

The aim of the study is to report on the feasibility, reliability, validity, and the norm-references of the Dutch version of the PedsQL^TM Multidimensional Fatigue Scale.     

Trends in PACS architecture

Radiological Picture Archiving and Communication Systems (PACS) have only relatively recently become abundant. Many hospitals have made the transition to PACS about a decade ago. During that decade requirements and available technology have changed considerably. In this paper we look at factors that influence the design of tomorrow's systems, especially those in larger multidisciplinary hospitals. We discuss their impact on PACS architecture (a technological perspective) as well as their impact on radiology (a management perspective).We emphasize that many of these influencing factors originate outside radiology and that radiology has little impact on these factors. That makes it the more important for managers in radiology to be aware of architectural aspects and it may change cooperation of radiology with, among others, the hospital's central IT department.     

Minimal sampling protocol for accurate estimation of urea production: a study with oral [13C]urea in fed and fasted piglets

BACKGROUND & AIMS: An oral [13C]urea protocol may provide a simple method for measurement of urea production. The validity of single pool calculations in relation to a reduced sampling protocol was assessed. METHODS: In eight fed and five fasted piglets, plasma urea enrichments from a 10 h sampling protocol were measured following an intragastric [13C]urea bolus. Blood [13C]bicarbonate was measured to trace gut [13C]urea oxidation. Two-compartment and regression (single pool) computations were performed. Pool sizes were compared to urea distribution over total body water (TBW). Shorter protocol duration was tested in regression simulations. RESULTS: Differences in urea kinetics between fed and fasted piglets did not reach statistical significance. Mean (+/-SE) urea pool from TBW times plasma urea concentration was 2.2+/-0.16 mmol kg(-1). Two-compartment modelling yielded similar results for pool size (despite the oxidation of a small amount of urea tracer). Urea appearance rate was 306+/-18 micromol kg(-1)h(-1). Regression calculations overestimated urea appearance rate vs. compartmental model (P<0.05). When samples <2 h were discarded, results were comparable to compartmental calculations even if protocol length was 6 h (325+/-24 micromol kg(-1)h(-1), NS). CONCLUSIONS: Regression calculations using plasma enrichments sampled between 2 and 6 h after oral [13C]urea administration provide accurate rates of urea production, and are not affected by tracer oxidation.     

Insulin induces a hypercontractile airway smooth muscle phenotype

This study aims to investigate the effects of insulin on bovine tracheal smooth muscle phenotype in vitro. Contractility of muscle strips and DNA-synthesis ([3H]thymidine incorporation) of isolated cells were used as parameters for smooth muscle phenotyping. Insulin (1 microM) was mitogenic for bovine tracheal smooth muscle and potentiated DNA-synthesis induced by other growth factors. In contrast, after pretreatment of unpassaged bovine tracheal smooth muscle cells in culture, the mitogenic response induced by growth factors was strongly diminished, with no difference in the basal incorporation. Pretreatment of bovine tracheal smooth muscle strips in organ culture with insulin increased maximal contraction to methacholine and KCl. These results show that insulin acutely augments DNA-synthesis in the presence of other growth factors. In contrast, insulin pretreatment induces a hypercontractile phenotype with a decreased mitogenic capacity. This mechanism may be involved in the putative negative association between asthma and type I diabetes. In addition, these findings may have implications for the use of aerosolized insulin in diabetes mellitus.