Search

The contribution of branched-axon monosynaptic inputs in the generation of short-term synchronization of motoneurones remains uncertain. Here, synchronization was measured for intercostal and abdominal motoneurones supplying the lower thorax and upper abdomen, mostly showing expiratory discharges. Synchronization in the anaesthetized cat, where the motoneurones receive a strong direct descending drive, is compared with that in anaesthetized or decerebrate rats, where the direct descending drive is much weaker. In the cat, some examples could be explained by branched-axon monosynaptic inputs, but many others could not, by virtue of peaks in cross-correlation histograms whose widths (relatively wide) and timing indicated common inputs with more complex linkages, e.g., disynaptic excitatory. In contrast, in the rat, correlations for pairs of internal intercostal nerves were dominated by very narrow peaks, indicative of branched-axon monosynaptic inputs. However, the presence of activity in both inspiration and expiration in many of the nerves allowed additional synchronization measurements between internal and external intercostal nerves. Time courses of synchronization for these often consisted of combinations of peaks and troughs, which have never been previously described for motoneurone synchronization and which we interpret as indicating combinations of inputs, excitation of one group of motoneurones being common with either excitation or inhibition of the other. Significant species differences in the circuits controlling the motoneurones are indicated, but in both cases, the roles of spinal interneurones are emphasised. The results demonstrate the potential of motoneurone synchronization for investigating inhibition and have important general implications for the interpretation of neural connectivity measurements by cross-correlation. [ABSTRACT FROM AUTHOR]

Cross-correlation of neural discharges was used to investigate the connections between expiratory bulbospinal neurons (EBSNs) in the caudal medulla and expiratory motoneurons innervating thoracic and abdominal muscles in anesthetized cats. Peaks were seen in the cross-correlation histograms for around half of the EBSN-nerve pairs for the following: at T8, the nerve branches innervating internal intercostal muscle and external abdominal oblique muscle and a more distal branch of the internal intercostal nerve; and at L1, a nerve branch innervating internal abdominal oblique muscle and a more distal branch of the ventral ramus. Fewer peaks were seen for the L1 nerve innervating external abdominal oblique, but a paucity of presumed α-motoneuron discharges could explain the rarity of the peaks in this instance. Taking into account individual EBSN conduction times to T8 and to L1, as well as peripheral conduction times, nearly all of the peaks were interpreted as representing monosynaptic connections. Individual EBSNs showed connections at both T8 and L1, but without any discernible pattern. The overall strength of the monosynaptic connection from EBSNs at L1 was found to be very similar to that at T8, which was previously argued to be substantial and responsible for the temporal patterns of expiratory motoneuron discharges. However, we argue that other inputs are required to create the stereotyped spatial patterns of discharges in the thoracic and abdominal musculature. [ABSTRACT FROM AUTHOR]

Endogenously produced nitric oxide (NO) is detectable in the exhaled air of resting humans, and the amount of exhaled NO increases during exercise. It is believed that NO is likely to have an important role in the normal physiological response to exercise. Despite accumulating evidence of exhaled NO during exercise, the effects and relevance of NO to exercise are not yet completely understood. Scientific debate surrounds the site of NO production and the stimuli for production. Resolution of these controversial issues will explain the significance of exhaled NO during exercise. [ABSTRACT FROM AUTHOR]

Background Recently, several proteins of the extracellular matrix have been characterised as active contributors to allergic airway disease. Microfibrillarassociated protein 4 (MFAP4) is an extracellular matrix protein abundant in the lung, whose biological functions remain poorly understood. In the current study we investigated the role of MFAP4 in experimental allergic asthma. Methods MFAP4-deficient mice were subjected to alum/ovalbumin and house dust mite induced models of allergic airway disease. In addition, human healthy and asthmatic primary bronchial smooth muscle cell cultures were used to evaluate MFAP4-dependent airway smooth muscle responses. Results MFAP4 deficiency attenuated classical hallmarks of asthma, such as eosinophilic inflammation, eotaxin production, airway remodelling and hyperresponsiveness. In wild-type mice, serum MFAP4 was increased after disease development and correlated with local eotaxin levels. MFAP4 was expressed in human bronchial smooth muscle cells and its expression was upregulated in asthmatic cells. Regarding the underlying mechanism, we showed that MFAP4 interacted with integrin αvβ5 and promoted asthmatic bronchial smooth muscle cell proliferation and CCL11 release dependent on phosphatidyloinositol-3-kinase but not extracellular signal-regulated kinase pathway. Conclusions MFAP4 promoted the development of asthmatic airway disease in vivo and pro-asthmatic functions of bronchial smooth muscle cells in vitro. Collectively, our results identify MFAP4 as a novel contributor to experimental asthma, acting through modulation of airway smooth muscle cells. [ABSTRACT FROM AUTHOR]

Background: Treatment of moderate or severe chronic obstructive pulmonary disease (COPD) with combinations of inhaled corticosteroids, long-acting beta-agonists, and long-acting anticholinergic bronchodilators is common but unstudied.Objective: To determine whether combining tiotropium with salmeterol or fluticasone-salmeterol improves clinical outcomes in adults with moderate to severe COPD compared with tiotropium alone.Design: Randomized, double-blind, placebo-controlled trial conducted from October 2003 to January 2006.Setting: 27 academic and community medical centers in Canada.Patients: 449 patients with moderate or severe COPD.Intervention: 1 year of treatment with tiotropium plus placebo, tiotropium plus salmeterol, or tiotropium plus fluticasone-salmeterol.Measurements: The primary end point was the proportion of patients who experienced an exacerbation of COPD that required treatment with systemic steroids or antibiotics.Results: The proportion of patients in the tiotropium plus placebo group who experienced an exacerbation (62.8%) did not differ from that in the tiotropium plus salmeterol group (64.8%; difference, -2.0 percentage points [95% CI, -12.8 to 8.8 percentage points]) or in the tiotropium plus fluticasone-salmeterol group (60.0%; difference, 2.8 percentage points [CI, -8.2 to 13.8 percentage points]). In sensitivity analyses, the point estimates and 95% confidence bounds shifted in the direction favoring tiotropium plus salmeterol and tiotropium plus fluticasone-salmeterol. Tiotropium plus fluticasone-salmeterol improved lung function (P = 0.049) and disease-specific quality of life (P = 0.01) and reduced the number of hospitalizations for COPD exacerbation (incidence rate ratio, 0.53 [CI, 0.33 to 0.86]) and all-cause hospitalizations (incidence rate ratio, 0.67 [CI, 0.45 to 0.99]) compared with tiotropium plus placebo. In contrast, tiotropium plus salmeterol did not statistically improve lung function or hospitalization rates compared with tiotropium plus placebo.Limitations: More than 40% of patients who received tiotropium plus placebo and tiotropium plus salmeterol discontinued therapy prematurely, and many crossed over to treatment with open-label inhaled steroids or long-acting beta-agonists.Conclusions: Addition of fluticasone-salmeterol to tiotropium therapy did not statistically influence rates of COPD exacerbation but did improve lung function, quality of life, and hospitalization rates in patients with moderate to severe COPD. International Standard Randomised Controlled Trial registration number: ISRCTN29870041. [ABSTRACT FROM AUTHOR]

Abstract: Nitric oxide (NO) is the smallest known gaseous signaling molecule released by mammalian and plant cells. To investigate the pathophysiologic role of exogenous NO gas (gNO) in bacterial and mammalian cell cultures, a validated in vitro delivery method is required. The system should be able to deliver gNO directly to bacterial and/or cell cultures in a continuous, predictable, and reproducible manner over a long period of time (days). To accomplish this, a gas delivery system was designed to provide optimal growth conditions for bacteria and/or mammalian cells. Parameters for cell exposure, such as concentration of gNO, nitrogen dioxide (NO2), oxygen (O2), temperature, and relative humidity (RH) were continuously monitored and evaluated. Uptake of gNO into various media was monitored by measuring the nitrite concentration using the Griess reagent technique. A selection of standard growth media [saline, tryptic soy broth (TSB), Middlebrook 7H9 (MB 7H9), and Dulbecco’s modified Eagle’s medium (DMEM)] exposed to various concentrations of gNO revealed a steady and consistent transfer of gNO into the aqueous phase over a 48-h period. Validation of optimal growth conditions within the device, as compared to a conventional incubator, were accomplished by growing and observing viability of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and human fibroblast cultures in the absence of gNO. These results indicate that an optimal growth environment for the above tested cells was accomplished inside the proposed delivery system. Dose-dependent toxicological data revealed a significant bacteriostatic effect on P. aeruginosa and S. aureus with continuous exposure to 80ppm gNO. No toxic effects were observed on dermal fibroblast proliferation at concentrations up to 400ppm gNO for 48h. In conclusion, the designed gNO exposure system is capable of supporting cellular viability for a representative range of prokaryote and eukaryotic cells. The exposure system is also capable of obtaining toxicological data. Therefore, the proposed device can be utilized to continuously expose cells to various levels of gNO for up to 72h to study the in vitro effects of gNO therapy. [Copyright &y& Elsevier]

Myositis associated with graft-versus-host-disease (GVHD) typically presents with proximal muscle weakness, myalgias, and a raised creatinine phosphokinase (CPK) level. We report a case of a 51 year old man who developed respiratory muscle weakness five years after an allogeneic bone marrow transplant for multiple myeloma. His symptoms included tachypnoea, abdominal paradox, and orthopnoea. Pulmonary function tests revealed diminished vital capacity and maximal inspiratory and expiratory pressures. Serum CPK levels were raised and a peripheral muscle biopsy specimen was consistent with GVHD. He improved with immunosuppressive therapy. [ABSTRACT FROM AUTHOR]