Software for interpreting cardiopulmonary exercise tests

<p>Abstract</p> <p>Background</p> <p>Cardiopulmonary exercise testing (CPET) has become an important modality for the evaluation and management of patients with a diverse array of medical problems. However, interpreting these tests is often difficult and time consuming, requiring significant expertise.</p> <p>Methods</p> <p>We created a computer software program (XINT) that assists in CPET interpretation. The program uses an integrative approach as recommended in the Official Statement of the American Thoracic Society/American College of Chest Physicians (ATS/ACCP) on Cardiopulmonary Exercise Testing. In this paper we discuss the principles behind the software. We also provide the detailed logic in an accompanying file (Additional File <supplr sid="S1">1</supplr>). The actual program and the open source code are also available free over the Internet at <url>http://www.xint.org</url>. For convenience, the required download files can also be accessed from this article.</p> <suppl id="S1"> <title> <p>Additional file 1</p> </title> <text> <p>XINTlogic. This file provides the detailed logic used by the XINT program. The variable names are described in Table <tblr tid="T1">1</tblr>. The actual source code may also be read directly simply by opening the source code with a text editor.</p> </text> <file name="1471-2466-7-15-S1.doc"> <p>Click here for file</p> </file> </suppl> <p>Results</p> <p>To test the clinical usefulness of XINT, we present the computer generated interpretations of the case studies discussed in the ATS/ACCP document in another accompanying file (Additional File <supplr sid="S2">2</supplr>). We believe the interpretations are consistent with the document's criteria and the interpretations given by the expert panel.</p> <suppl id="S2"> <title> <p>Additional file 2</p> </title> <text> <p>XINTinterpretations. These are the XINT generated reports based on the five examples provided in the ATS/ACCP statement on cardiopulmonary exercise testing <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>.</p> </text> <file name="1471-2466-7-15-S2.doc"> <p>Click here for file</p> </file> </suppl> <p>Conclusion</p> <p>Computers have become an integral part of modern life. Peer-reviewed scientific journals are now able to present not just medical concepts and experimental studies, but actual functioning medical interpretive software. This has enormous potential to improve medical diagnoses and patient care. We believe XINT is such a program that will give clinically useful interpretations when used by the medical community at large.</p

Alveolar macrophages in lung cancer: opportunities challenges

Alveolar macrophages (AMs) are critical components of the innate defense mechanism in the lung. Nestled tightly within the alveoli, AMs, derived from the yolk-sac or bone marrow, can phagocytose foreign particles, defend the host against pathogens, recycle surfactant, and promptly respond to inhaled noxious stimuli. The behavior of AMs is tightly dependent on the environmental cues whereby infection, chronic inflammation, and associated metabolic changes can repolarize their effector functions in the lungs. Several factors within the tumor microenvironment can re-educate AMs, resulting in tumor growth, and reducing immune checkpoint inhibitors (ICIs) efficacy in patients treated for non-small cell lung cancer (NSCLC). The plasticity of AMs and their critical function in altering tumor responses to ICIs make them a desirable target in lung cancer treatment. New strategies have been developed to target AMs in solid tumors reprograming their suppressive function and boosting the efficacy of ICIs. Here, we review the phenotypic and functional changes in AMs in response to sterile inflammation and in NSCLC that could be critical in tumor growth and metastasis. Opportunities in altering AMs’ function include harnessing their potential function in trained immunity, a concept borrowed from memory response to infections, which could be explored therapeutically in managing lung cancer treatment

A kinetic study of cation transport in erythrocytes from uremic patients

A kinetic study of cation transport from uremic patients. We previously described in red blood cells (RBCs) from uremic patients on dialysis a reduction in sodium (Na) efflux through the Na, potassium (K) cotransport system (Na,K CoT) while Na efflux through the Na,K pump was normal. We then examined Na efflux in fresh cells and in cells loaded to obtain one level of intracellular sodium (Nai) concentration at about 25 mmol/liter cell. In the present study we used similar cation flux methodology to examine the kinetics of cation efflux through the Na,K pump and Na,K CoT in uremic patients on dialysis. RBCs were Na-loaded to attain five different levels of Nat concentration over a range of 5 to 50 mmol/liter cells using the ionophore nystatin. At each level of Na-loading, the Nai achieved was similar in RBCs from controls and patients. Ouabain–sensitive Na efflux through the Na,K pump showed no difference in rate between normals and dialysis patients. When the kinetic parameters of this transport pathway were considered, the apparent affinity (K0.5) for sodium was not significantly different between controls and patients (18.4 ± 2.3 vs. 20.0 ± 2.6 mmol/liter cell) and the maximal velocity of efflux (Vmax) was also not different between controls and patients (9.6 ± 0.7 vs. 8.5 ± 1.2 mmol&sol;liter cell&sol;hr). Comparison of Nai-activated Na versus K efflux rates through the Na,K CoT in normal subjects demonstrated similar saturation kinetics, (K0.5 15.8 ± 3.3 vs. 12.2 ± 2.8 mmol/liter cell, Vmax0.81 ± 0.1 vs. 0.78 ± 0.1 mmol/liter cell/hr) consistent with the known stoichiometric ratio of 1 Na:l K:2 C1 described for this mechanism. In dialysis patients Nai-activated, Na,K CoT-mediated Na efflux was markedly reduced. Analysis of the kinetic parameters of Na1-activated Na efflux showed that the reduced RBC Na,K CoT is due to reduction in Vmax and not to a change in K0.5 Maximum furosemide–sensitive K efflux rate was also reduced in dialysis patients. However, instead of exhibiting the anticipated saturation kinetics observed for Na, the K efflux rates were high at low levels of Nai and remained unchanged with increasing Nai concentrations. Ouabain- and furosemide-resistant Na and K effluxes were not significantly different between normals and dialysis patients. We conclude that Na efflux through RBC Na,K pump is intact over a wide range of Nai concentrations in dialysis patients. On the other hand, the furosemide–sensitive co-efflux of Na and K, which in normal RBCs displayed a typical 1 Na to 1 K transport characteristic, was quantitatively and qualitatively altered in dialysis patients. The maximum efflux rate of both Na and K was reduced and in addition, the usual stoichiometric ratio for Na and K exit through this furosemide–sensitive pathway was no longer observed

Counting Arithmetical Structures on Paths and Cycles

Let G be a finite, connected graph. An arithmetical structure on G is a pair of positive integer vectors d, r such that (diag (d) - A) r=0 , where A is the adjacency matrix of G. We investigate the combinatorics of arithmetical structures on path and cycle graphs, as well as the associated critical groups (the torsion part of the cokernels of the matrices (diag (d) - A)). For paths, we prove that arithmetical structures are enumerated by the Catalan numbers, and we obtain refined enumeration results related to ballot sequences. For cycles, we prove that arithmetical structures are enumerated by the binomial coefficients ((2n-1)/(n-1)) , and we obtain refined enumeration results related to multisets. In addition, we determine the critical groups for all arithmetical structures on paths and cycles

Counting Arithmetical Structures on Paths and Cycles

Let G be a finite, connected graph. An arithmetical structure on G is a pair of positive integer vectors d, r such that (diag (d) - A) r=0 , where A is the adjacency matrix of G. We investigate the combinatorics of arithmetical structures on path and cycle graphs, as well as the associated critical groups (the torsion part of the cokernels of the matrices (diag (d) - A)). For paths, we prove that arithmetical structures are enumerated by the Catalan numbers, and we obtain refined enumeration results related to ballot sequences. For cycles, we prove that arithmetical structures are enumerated by the binomial coefficients ((2n-1)/(n-1)) , and we obtain refined enumeration results related to multisets. In addition, we determine the critical groups for all arithmetical structures on paths and cycles

Divergent functions for airway epithelial matrix metalloproteinase 7 and retinoic acid in experimental asthma.

The innate immune response of airway epithelial cells to airborne allergens initiates the development of T cell responses that are central to allergic inflammation. Although proteinase allergens induce the expression of interleukin 25, we show here that epithelial matrix metalloproteinase 7 (MMP7) was expressed during asthma and was required for the maximum activity of interleukin 25 in promoting the differentiation of T helper type 2 cells. Allergen-challenged Mmp7(-/-) mice had less airway hyper-reactivity and production of allergic inflammatory cytokines and higher expression of retinal dehydrogenase 1. Inhibition of retinal dehydrogenase 1 restored the asthma phenotype of Mmp7(-/-) mice and inhibited the responses of lung regulatory T cells, whereas exogenous administration of retinoic acid attenuated the asthma phenotype. Thus, MMP7 coordinates allergic lung inflammation by activating interleukin 25 while simultaneously inhibiting retinoid-dependent development of regulatory T cells

Proteomic identification of in vivo substrates for matrix metalloproteinases 2 and 9 reveals a mechanism for resolution of inflammation.

Clearance of allergic inflammatory cells from the lung through matrix metalloproteinases (MMPs) is necessary to prevent lethal asphyxiation, but mechanistic insight into this essential homeostatic process is lacking. In this study, we have used a proteomics approach to determine how MMPs promote egression of lung inflammatory cells through the airway. MMP2- and MMP9-dependent cleavage of individual Th2 chemokines modulated their chemotactic activity; however, the net effect of complementing bronchoalveolar lavage fluid of allergen-challenged MMP2(-/-)/MMP9(-/-) mice with active MMP2 and MMP9 was to markedly enhance its overall chemotactic activity. In the bronchoalveolar fluid of MMP2(-/-)/MMP9(-/-) allergic mice, we identified several chemotactic molecules that possessed putative MMP2 and MMP9 cleavage sites and were present as higher molecular mass species. In vitro cleavage assays and mass spectroscopy confirmed that three of the identified proteins, Ym1, S100A8, and S100A9, were substrates of MMP2, MMP9, or both. Function-blocking Abs to S100 proteins significantly altered allergic inflammatory cell migration into the alveolar space. Thus, an important effect of MMPs is to differentially modify chemotactic bioactivity through proteolytic processing of proteins present in the airway. These findings provide a molecular mechanism to explain the enhanced clearance of lung inflammatory cells through the airway and reveal a novel approach to target new therapies for asthma

A functional correlate of severity in alternating hemiplegia of childhood

OBJECTIVE: Mutations in ATP1A3, the gene that encodes the α3 subunit of the Na(+)/K(+) ATPase, are the primary cause of alternating hemiplegia of childhood (AHC). Correlations between different mutations and AHC severity were recently reported, with E815K identified in severe and D801N and G947R in milder cases. This study aims to explore the molecular pathological mechanisms in AHC and to identify functional correlates for mutations associated with different levels of disease severity. METHODS: Human wild type ATP1A3, and E815K, D801N and G947R mutants were expressed in Xenopus laevis oocytes and Na(+)/K(+) ATPase function measured. Structural homology models of the human α3 subunit containing AHC mutations were created. RESULTS: The AHC mutations examined all showed similar levels of reduction in forward cycling. Wild type forward cycling was reduced by coexpression with any mutant, indicating dominant negative interactions. Proton transport was measured and found to be selectively impaired only in E815K. Homology modeling showed that D801 and G947 lie within or near known cation binding sites while E815 is more distal. Despite its effect on proton transport, E815K was also distant from the proposed proton transport route. INTERPRETATION: Loss of forward cycling and dominant negativity are common and likely necessary pathomechanisms for AHC. In addition, loss of proton transport correlated with severity of AHC. D801N and G947R are likely to directly disrupt normal Na(+)/K(+) binding while E815K may disrupt forward cycling and proton transport via allosteric mechanisms yet to be elucidated