Inhibition of granulocyte migration by tiotropium bromide

<p>Abstract</p> <p>Study objectives</p> <p>Neutrophil influx into the airways is an important mechanism in the pathophysiology of the inflammatory process in the airways of patients with chronic obstructive pulmonary disease (COPD). Previously it was shown that anticholinergic drugs reduce the release of non-neuronal paracrine mediators, which modulate inflammation in the airways. On this basis, we investigated the ability of the long-acting anticholinergic tiotropium bromide to inhibit a) alveolar macrophage (AM)-mediated chemotaxis of neutrophils, and b) cellular release of reactive oxygen species (ROS).</p> <p>Method</p> <p>AM and neutrophils were collected from 71 COPD patients. Nanomolar concentrations of tiotropium bromide were tested in AM cultured up to 20 h with LPS (1 μg/ml). AM supernatant was tested for TNFα, IL8, IL6, LTB4, GM-CSF, MIPα/β and ROS. It was further used in a 96-well chemotaxis chamber to stimulate the migration of fluorescence labelled neutrophils. Control stimulants consisted of acetylcholine (ACh), carbachol, muscarine or oxotremorine and in part PMA (phorbol myristate acetate, 0.1 μg/ml). Potential contribution of M_1-3-receptors was ascertained by a) analysis of mRNA transcription by RT-PCR, and b) co-incubation with selective M-receptor inhibitors.</p> <p>Results</p> <p>Supernatant from AM stimulated with LPS induced neutrophilic migration which could be reduced by tiotropium in a dose dependent manner: 22.1 ± 10.2 (3 nM), 26.5 ± 18,4 (30 nM), and 37.8 ± 24.0 (300 nM, p < 0.001 compared to non-LPS activated AM). Concomitantly TNFα release of stimulated AM dropped by 19.2 ± 7.2% of control (p = 0.001). Tiotropium bromide did not affect cellular IL8, IL6, LTB4, GM-CSF and MIPα/β release in this setting. Tiotropium (30 nM) reduced ROS release of LPS stimulated AM by 36.1 ± 15.2% (p = 0.002) and in carbachol stimulated AM by 46.2 ± 30.2 (p < 0.001). M3R gene expression dominated over M2R and M1R. Chemotaxis inhibitory effect of tiotropium bromide was mainly driven by M3R inhibition.</p> <p>Conclusion</p> <p>Our data confirm that inhibiting muscarinic cholinergic receptors with tiotropium bromide reduces TNFα mediated chemotactic properties and ROS release of human AM, and thus may contribute to lessen cellular inflammation.</p

List coloring in the absence of a linear forest.

The k-Coloring problem is to decide whether a graph can be colored with at most k colors such that no two adjacent vertices receive the same color. The Listk-Coloring problem requires in addition that every vertex u must receive a color from some given set L(u)⊆{1,…,k}. Let Pn denote the path on n vertices, and G+H and rH the disjoint union of two graphs G and H and r copies of H, respectively. For any two fixed integers k and r, we show that Listk-Coloring can be solved in polynomial time for graphs with no induced rP1+P5, hereby extending the result of Hoàng, Kamiński, Lozin, Sawada and Shu for graphs with no induced P5. Our result is tight; we prove that for any graph H that is a supergraph of P1+P5 with at least 5 edges, already List 5-Coloring is NP-complete for graphs with no induced H

An invasive and a noninvasive approach for the automatic differentiation of obstructive and central hypopneas

The automatic differentiation of obstructive and central respiratory events is a major challenge in the diagnosis of sleep-disordered breathing. Esophageal pressure (Pes) measurement is the gold-standard method to identify these events. This study presents a new classifier that automatically differentiates obstructive and central hypopneas with the Pes signal and a new approach for an automatic noninvasive classifierwith nasal airflow. An overall of 28 patients underwent night polysomnography with Pes recording, and a total of 769 hypopneas were manually scored by human experts to create a gold-standard annotation set. Features were automatically extracted fromthe Pes signal to train and test the classifiers (discriminant analysis, support vector machines, and adaboost). After a significantly (p < 0.01) higher incidence of inspiratory flow limitation episodes in obstructive hypopneas was objectively, invasively assessed compared to central hypopneas, the feasibility of an automatic noninvasive classifier with features extracted from the airflow signal was demonstrated. The automatic invasive classifier achieved a mean sensitivity, specificity, and accuracy of 0.90 after a 100-fold cross validation. The automatic noninvasive feasibility study obtained similar hypopnea differentiation results as a manual noninvasive classification algorithm. Hence, both systems seem promising for the automatic differentiation of obstructive and central hypopneas.Peer ReviewedPostprint (published version

Position paper on the use of mandibular advancement devices in adults with sleep-related breathing disorders: A position paper of the German Society of Dental Sleep Medicine (Deutsche Gesellschaft Zahnaerztliche Schlafmedizin, DGZS)

Custom-made mandibular advancement devices are an effective treatment option for snoring, upper airway resistance syndrome, and obstructive sleep apnea (OSA). Evidence-based data indicates their efficacy, and international sleep societies recommend oral appliance (OA) therapy for patients with sleep-related breathing disorders. The following position paper by the German Society of Dental Sleep Medicine (DGZS) is to guide the interdisciplinary team (sleep physician and sleep disorder dentist) in detail when to prescribe oral appliances. This position paper supports the responsible use of OA as an effective treatment option for patients with sleep-related breathing disorders. The paper advises of proper indication regarding OSA severity, body mass index (BMI), and dentition. It emphasizes the interdisciplinary approach of oral appliance therapy and suggests treatment under the guidance of dentists trained in dental sleep medicine

A Satisfiability-based Approach for Embedding Generalized Tanglegrams on Level Graphs

A tanglegram is a pair of trees on the same set of leaves with matching leaves in the two trees joined by an edge. Tanglegrams are widely used in computational biology to compare evolutionary histories of species. In this paper we present a formulation of two related combinatorial embedding problems concerning tanglegrams in terms of CNF-formulas. The first problem is known as planar embedding and the second as crossing minimization problem. We show that our satisfiability formulation of these problems can handle a much more general case with more than two, not necessarily binary or complete, trees defined on arbitrary sets of leaves and allowed to vary their layouts

Real time geotechnical field data acquistion using a distributed approach

A distributed geotechnical remote analysis of data system (Distributed G-RAD) can benefit both owners and contractors in providing better quality control and assurance on geotechnical projects. The Distributed G-RAD approach involves efficient data acquisition using PDAs with GPS capability, radio frequency identification (RFID) tags for labeling soil samples, laser scanning for measuring lift thickness and volumes of stockpiles and borrow pits. Spatial data storage is provided using a geographic information system (GIS). Portions of this system are already developed while other parts are still being considered. This paper also describes how RFID and laser scanning technologies can be used in the larger Distributed G-RAD system

Introducing a core curriculum for respiratory sleep practitioners

The background and purpose of the HERMES (Harmonising Education in Respiratory Medicine for European Specialists) initiative has been discussed at length in previous articles [1-3]. This article aims to provide more detailed and specific insight into the process and methodology of the Sleep HERMES Task Force in developing a core curriculum in respiratory sleep medicine

Impaired Communication Between the Dorsal and Ventral Stream: Indications from Apraxia

Patients with apraxia perform poorly when demonstrating how an object is used, particularly when pantomiming the action. However, these patients are able to accurately identify, and to pick up and move objects, demonstrating intact ventral and dorsal stream visuomotor processing. Appropriate object manipulation for skilled use is thought to rely on integration of known and visible object properties associated with “ventro-dorsal” stream neural processes. In apraxia, it has been suggested that stored object knowledge from the ventral stream may be less readily available to incorporate into the action plan, leading to an over-reliance on the objects’ visual affordances in object-directed motor behavior. The current study examined grasping performance in left hemisphere stroke patients with (N = 3) and without (N = 9) apraxia, and in age-matched healthy control participants (N = 14), where participants repeatedly grasped novel cylindrical objects of varying weight distribution. Across two conditions, object weight distribution was indicated by either a memory-associated cue (object color) or visual-spatial cue (visible dot over the weighted end). Participants were required to incorporate object-weight associations to effectively grasp and balance each object. Control groups appropriately adjusted their grasp according to each object’s weight distribution across each condition, whereas throughout the task two of the three apraxic patients performed poorly on both the memory-associated and visual-spatial cue conditions. A third apraxic patient seemed to compensate for these difficulties but still performed differently to control groups. Patients with apraxia performed normally on the neutral control condition when grasping the evenly weighted version. The pattern of behavior in apraxic patients suggests impaired integration of visible and known object properties attributed to the ventro-dorsal stream: in learning to grasp the weighted object accurately, apraxic patients applied neither pure knowledge-based information (the memory-associated condition) nor higher-level information given in the visual-spatial cue condition. Disruption to ventro-dorsal stream predicts that apraxic patients will have difficulty learning to manipulate new objects on the basis of information other than low-level visual cues such as shape and size