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

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

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

Treatment options in Cheyne-Stokes respiration

About half of the patients suffering from heart failure present with sleep-disordered breathing. In most cases obstructive and central breathing disturbances (including Cheyne-Stokes respiration [CSR]) coexist. CSR is defined by a waxing and waning pattern of the tidal volume. While its pathophysiology has not been elucidated completely, increased ventilatory sensitivity for CO 2 and therefore an imbalance of the respiratory drive and effort, a chronic hyperventilatory state, and changes of the apnoeic threshold are considered to play a relevant role. However, CSR in heart failure impairs survival and quality of life of the patients and is therefore a major challenge of respiratory sleep medicine. If CSR persists despite optimal medical and interventional therapy of the underlying cardiac disorder, oxygen supply, continuous positive airway pressure (CPAP), and bilevel pressure are often trialled. However, there is insufficient evidence to recommend oxygen or bilevel treatment. CPAP has proven to improve left ventricular function. In addition, retrospective analyses suggested a reduction of mortality under CPAP in heart failure patients with CSR. However, these findings could not be reproduced in the prospective controlled CanPAP trial. More recently, adaptive servoventilation (ASV) has been introduced for treatment of CSR or coexisting sleep-related breathing disorders. ASV devices aim at counterbalancing the ventilatory overshoot and undershoot by applying variable pressure support with higher tidal volume (TV) during hypoventilation and reduced TV during hyperventilation. ASV has proven to be superior to CPAP but the long-term efficacy and the influences on cardiac parameters and survival are still under investigation

Chronic hypoventilation syndromes and sleep-related hypoventilation

Chronic hypoventilation affects patients with disorders on any level of the respiratory system. The generation of respiratory impulses can be impaired in congenital disorders, such as central congenital alveolar hypoventilation, in alterations of the brain stem or complex diseases like obesity hypoventilation. The translation of the impulses via spinal cord and nerves to the respiratory muscles can be impaired in neurological diseases. Thoraco-skeletal or muscular diseases may inhibit the execution of the impulses. All hypoventilation disorders are characterized by a reduction of the minute ventilation with an increase of daytime hypercapnia. As sleep reduces minute ventilation substantially in healthy persons and much more pronounced in patients with underlying thoraco-pulmonary diseases, hypoventilation manifests firstly during sleep. Therefore, sleep related hypoventilation may be an early stage of chronic hypoventilation disorders. After treatment of any prevailing underlying disease, symptomatic therapy with non-invasive ventilation (NIV) is required. The adaptation of the treatment should be performed under close medical supervision. Pressure support algorithms have become most frequently used. The most recent devices automatically apply pressure support and vary inspiratory and expiratory pressures and breathing frequency in order to stabilize upper airways, normalize ventilation, achieve best synchronicity between patient and device and aim at optimizing patients' adherence