BackgroundBoth Peak Oxygen Uptake (peak VO2), from cardiopulmonary exercise testing (CPET) and the distance walked during a Six-Minute Walk Test (6 MWD) are used for following the natural history of various diseases, timing of procedures such as transplantation and for assessing the response to therapeutic interventions. However, their relationship has not been clearly defined.MethodsWe determined the ability of 6 MWD to predict peak VO2 using data points from 1,083 patients with diverse cardiopulmonary disorders. The patient data came from a study we performed and 10 separate studies where we were able to electronically convert published scattergrams to bivariate points. Using Linear Mixed Model analysis (LMM), we determined what effect factors such as disease entity and different inter-site testing protocols contributed to the magnitude of the standard error of estimate (SEE).ResultsThe LMM analysis found that only 0.16 ml/kg/min or about 4% of the SEE was due to all of the inter-site testing differences. The major source of error is the inherent variability related to the two tests. Therefore, we were able to create a generalized equation that can be used to predict peak VO2 among patients with different diseases, who have undergone various exercise protocols, with minimal loss of accuracy. Although 6 MWD and peak VO2 are significantly correlated, the SEE is unacceptably large for clinical usefulness in an individual patient. For the data as a whole it is 3.82 ml/kg/min or 26.7% of mean peak VO2. Conversely, the SEE for predicting the mean peak VO2 from mean 6 MWD for the 11 study groups is only 1.1 ml/kg/min.ConclusionsA generalized equation can be used to predict peak VO2 from 6 MWD. Unfortunately, like other prediction equations, it is of limited usefulness for individual patients. However, the generalized equation can be used to accurately estimate mean peak VO2 from mean 6 MWD, among groups of patients with diverse diseases without the need for cardiopulmonary exercise testing. The equation is:

BackgroundAdenosine is generated in response to cellular stress and damage and is elevated in the lungs of patients with chronic lung disease. Adenosine signaling through its cell surface receptors serves as an amplifier of chronic lung disorders, suggesting adenosine-based therapeutics may be beneficial in the treatment of lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Previous studies in mouse models of chronic lung disease demonstrate that the key components of adenosine metabolism and signaling are altered. Changes include an up-regulation of CD73, the major enzyme of adenosine production and down-regulation of adenosine deaminase (ADA), the major enzyme for adenosine metabolism. In addition, adenosine receptors are elevated.Methodology/Principal FindingsThe focus of this study was to utilize tissues from patients with COPD or IPF to examine whether changes in purinergic metabolism and signaling occur in human disease. Results demonstrate that the levels of CD73 and A2BR are elevated in surgical lung biopsies from severe COPD and IPF patients. Immunolocalization assays revealed abundant expression of CD73 and the A2BR in alternatively activated macrophages in both COPD and IPF samples. In addition, mediators that are regulated by the A2BR, such as IL-6, IL-8 and osteopontin were elevated in these samples and activation of the A2BR on cells isolated from the airways of COPD and IPF patients was shown to directly induce the production of these mediators.Conclusions/SignificanceThese findings suggest that components of adenosine metabolism and signaling are altered in a manner that promotes adenosine production and signaling in the lungs of patients with COPD and IPF, and provide proof of concept information that these disorders may benefit from adenosine-based therapeutics. Furthermore, this study provides the first evidence that A2BR signaling can promote the production of inflammatory and fibrotic mediators in patients with these disorders.

Traumatic brain injury (TBI) is a global problem and causes long-term disability in millions of individuals. This is a major problem for both military- and civilian-related populations. The prevalence of sleep disorders in individuals with TBI is very high, yet mostly unrecognized. Approximately 46% of all chronic TBI patients have sleep disorders, which require nocturnal polysomnography and the Multiple Sleep Latency Test for diagnosis. These disorders include sleep apnoea (23% of all TBI patients), post-traumatic hypersomnia (11%), narcolepsy (6%) and periodic limb movements (7%). Over half of all TBI patients will have insomnia complaints, most often with less severe injury and after personal assault, and half of these may be related to a circadian rhythm disorder. Hypothalamic injury with decreased levels of wake-promoting neurotransmitters such as hypocretin (orexin) and histamine may be involved in the pathophysiology of excessive sleepiness associated with TBI. These sleep disorders result in additional neurocognitive deficits and functional impairment, which might be attributed to the original brain injury itself and thus be left without specific treatment. Most standard treatment regimens of sleep disorders appear to be effective in these patients, including continuous positive airway pressure for sleep apnoea, pramipexole for periodic limb movements and cognitive behavioural therapy for insomnia. The role of wake-promoting agents and CNS stimulants for TBI-associated narcolepsy, post-traumatic hypersomnia and excessive daytime sleepiness requires further study with larger numbers of patients to determine effectiveness and benefit in this population. Future research with multiple collaborating centres should attempt to delineate the pathophysiology of TBI-associated sleep disorders, including CNS-derived hypersomnia and circadian rhythm disturbances, and determine definitive, effective treatment for associated sleep disorders.

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Mast cell degranulation is a highly regulated, calciumdependent process, which is important for the acute release of inflammatory mediators during the course of many pathological conditions. We previously found that Synaptotagmin-2, a calcium sensor in neuronal exocytosis, was expressed in a mast cell line. We postulated that this protein may be involved in the control of mast cell-regulated exocytosis, and we generated Synaptotagmin-2 knock-out mice to test our hypothesis. Mast cells from this mutant animal conferred an abnormally decreased passive cutaneous anaphylaxis reaction on mast cell-deficient mice that correlated with a specific defect in mast cell-regulated exocytosis, leaving constitutive exocytosis and nonexocytic mast cell effector responses intact. This defect was not secondary to abnormalities in the development, maturation, migration, morphology, synthesis, and storage of inflammatory mediators, or intracellular calcium transients of the mast cells. Unlike neurons, the lack of Synaptotagmin-2 in mast cells was not associated with increased spontaneous exocytosis. Mast cells (MCs)2 participate in adaptive and innate immune responses. Their secreted products play important roles in immunoglobulin E (IgE)-dependent inflammatory reactions such as allergic asthma and anaphylaxis (1) and are also involved in other forms of inflammation such as immune arthritis (2, 3) and innate immune responses to bacterial infections (4, 5). Upon activation, MCs exhibit three main secretory responses: release of granule contents (i.e. degranulation), secretion of prostaglandins and leukotrienes, and secretion of cytokines and growth factors (6). The exocytic release of preformed mediators (e.g. histamine and proteases) stored in secretory granules is immediate and regulated at the step of fusion between the membrane of the granule and the plasma membrane. Thus, it is an example of regulated exocytosis, like neuronal synaptic neurotransmitter release and insulin secretion (7). Another early event is the release of metabolites of arachidonic acid (e.g. prostaglandin D 2 (PGD 2 ) and leukotriene C 4 (LTC 4 )). These eicosanoids cross the plasma membrane using transmembrane transporters (8), and their production is regulated by the activation of their synthetic enzymes (9). A late response after MC activation is the secretion of cytokines and growth factors (e.g. tumor necrosis factor-␣ (TNF-␣) and interleukin-4 (IL-4)). The gap in time of minutes to hours between stimulation and the secretion of these mediators is explained by the fact that regulation is at the transcriptional and post-transcriptional levels, with secretion occurring via constitutive exocytosis (10).A common intracellular mediator linking the stimulation event to these three MC responses is calcium (Ca 2ϩ ) that is released into the cytoplasm from intracellular stores and introduced from the extracellular environment via specialized channels. Increase in the cytoplasmic concentration of Ca 2ϩ ([Ca 2ϩ ] i ) is required for the activation of phospholi...

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TIRI is a feasible noncontact technology to monitor airflow during polysomnography. In its current methodologic incarnation, it demonstrates a high degree of chance-corrected agreement with the oronasal thermistor in the detection of apnea and hypopneas but demonstrates a lesser degree of chance-corrected agreement with Pn. Further overnight validation studies must be performed to evaluate its potential in clinical sleep medicine.

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