The Macrophage in Cystic Fibrosis

Background: Cystic fibrosis (CF) is caused by absent/defective CF transmembrane conductance regulator protein (CFTR). CF is characterized by thick airway mucus, chronic infection and neutrophil inflammation leading to respiratory failure. I analysed airway macrophages (MΦs) and their expression of pattern recognition receptors (PRRs) in CF, since these cells are crucial to airway immune defence and they can orchestrate inflammation. I also performed transcript analysis of CF monocyte-derived MΦs (MDMs). Methods: Sputum was induced in CF paediatric and adult cohorts. Phenotype and function of CF MΦ were determined by flow cytometry and compared to controls. Monocytes (>92% purity) were grown in vitro to generate MDMs (n=15). Transcripts encoding the entire human genome were analysed (n=5) and expression of individual genes were confirmed by RT-PCR. Results: In classical CF (n=10) there was an increase in the proportion of monocyte-like small MΦs (of total MΦ) compared to controls (n=10) (73 ± 18% and 16 ± 8%, respectively, p0.05). PRRs were absent on small MΦs from CF and control. In contrast, clear expression could be detected on large MΦs from control but not CF. In line with this, CF small MΦs showed a strongly reduced uptake of particles compared to controls. Microarray analysis of MDMs revealed α- and β-tryptase as being significantly higher under constitutive and stimulated conditions in CF compared to control. However, using RT-PCR, expression of α- and β-tryptase was similar between groups. Conclusions: The phenotype of small MΦs in CF suggests that these cells are newly recruited monocytes from blood. Low expression of PRRs on these cells in CF and their reduced uptake indicates a reduced capacity to clear inhaled particles, which may contribute to further damage in CF. Further to this I was unable to confirm any transcript differences between CF and control MDMs due to mutant CFTR

Adding an antiretroviral drug regimen for a patient with HIV in OpenMRS.

<p>(Note: The record shown here is only an example and does not represent a real patient.)</p

A distance continuing medical education presentation on RAFT by Walter Zingg on the subject of central line–associated infections.

<p>A distance continuing medical education presentation on RAFT by Walter Zingg on the subject of central line–associated infections.</p

COPD exacerbation severity and frequency is associated with impaired macrophage efferocytosis of eosinophils

Background: Eosinophilic airway inflammation is observed in 10-30% of COPD subjects. Whether increased eosinophils or impairment in their clearance by macrophages is associated with the severity and frequency of exacerbations is unknown. Methods: We categorised 103 COPD subjects into 4 groups determined by the upper limit of normal for their cytoplasmic macrophage red hue (<6%), an indirect measure of macrophage efferocytosis of eosinophils, and area under the curve sputum eosinophil count (≥3%/year). Eosinophil efferocytosis by monocyte-derived macrophages was studied in 17 COPD subjects and 8 normal controls. Results: There were no differences in baseline lung function, health status or exacerbation frequency between the groups: A-low red hue, high sputum eosinophils (n = 10), B-high red hue, high sputum eosinophils (n = 16), C-low red hue, low sputum eosinophils (n = 19) and D- high red hue, low sputum eosinophils (n = 58). Positive bacterial culture was lower in groups A (10%) and B (6%) compared to C (44%) and D (21%) (p = 0.01). The fall in FEV1 from stable to exacerbation was greatest in group A (ΔFEV1 [95 % CI] -0.41 L [-0.65 to -0.17]) versus group B (-0.16 L [-0.32 to -0.011]), C (-0.11 L [-0.23 to -0.002]) and D (-0.16 L [-0.22 to -0.10]; p = 0.02). Macrophage efferocytosis of eosinophils was impaired in COPD versus controls (86 [75 to 92]% versus 93 [88 to 96]%; p = 0.028); was most marked in group A (71 [70 to 84]%; p = 0.0295) and was inversely correlated with exacerbation frequency (r = -0.63; p = 0.006). Conclusions: Macrophage efferocytosis of eosinophils is impaired in COPD and is related to the severity and frequency of COPD exacerbations

Carbon Dioxide as a Tool to Deter the Movement of Invasive Bigheaded Carps

<p>Nonnative bigheaded carps are established in the Mississippi River and there is substantial concern about their potential entry into the interconnected Laurentian Great Lakes. While electrical barriers currently exist as a preventative measure, there is need for additional control mechanisms to promote barrier security through redundancy. We tested the effectiveness of infused carbon dioxide gas (CO₂) as a tool to influence the movement and behavior invasive bigheaded carps, namely Bighead Carp <i>Hypophthalmichthys nobilis</i> and Silver Carp <i>H. molitrix</i>, as well as native Bigmouth Buffalo <i>Ictiobus cyprinellus</i>, Channel Catfish <i>Ictalurus punctatus</i>, Paddlefish <i>Polyodon spathula</i>, and Yellow Perch <i>Perca flavescens</i> in an experimental pond. Individuals were monitored with acoustic telemetry before, during, and after CO₂ addition to the pond. We noted distinct changes in fish behavior following CO₂ addition. Each species except Paddlefish maintained farther distances from the CO₂ infusion manifold relative to controls. Both bigheaded carp species had slower persistence velocities (persistence of a movement in a given direction) following CO₂ infusion and Bighead Carp used a smaller area of the pond immediately after CO₂ addition. Pond pH progressively decreased up to 1.5 units following CO₂ infusion. This work provides evidence that could inform future research to enhance existing control measures used to deter high-risk invasive fishes, such as bigheaded carps.</p> <p>Received July 27, 2015; accepted January 11, 2016 Published online April 27, 2016</p

Impaired P2X1 Receptor–Mediated Adhesion in Eosinophils from Asthmatic Patients

Eosinophils play an important role in the pathogenesis of asthma and can be activated by extracellular nucleotides released following cell damage or inflammation. For example, increased ATP concentrations were reported in bronchoalveolar lavage fluids of asthmatic patients. Although eosinophils are known to express several subtypes of P2 receptors for extracellular nucleotides, their function and contribution to asthma remain unclear. In this article, we show that transcripts for P2X1, P2X4, and P2X5 receptors were expressed in healthy and asthmatic eosinophils. The P2X receptor agonist α,β-methylene ATP (α,β-meATP; 10 μM) evoked rapidly activating and desensitizing inward currents (peak 18 ± 3 pA/pF at −60 mV) in healthy eosinophils, typical of P2X1 homomeric receptors, which were abolished by the selective P2X1 antagonist NF449 (1 μM) (3 ± 2 pA/pF). α,β-meATP–evoked currents were smaller in eosinophils from asthmatic patients (8 ± 2 versus 27 ± 5 pA/pF for healthy) but were enhanced following treatment with a high concentration of the nucleotidase apyrase (17 ± 5 pA/pF for 10 IU/ml and 11 ± 3 pA/pF for 0.32 IU/ml), indicating that the channels are partially desensitized by extracellular nucleotides. α,β-meATP (10 μM) increased the expression of CD11b activated form in eosinophils from healthy, but not asthmatic, donors (143 ± 21% and 108 ± 11% of control response, respectively). Furthermore, α,β-meATP increased healthy (18 ± 2% compared with control 10 ± 1%) but not asthmatic (13 ± 1% versus 10 ± 0% for control) eosinophil adhesion. Healthy human eosinophils express functional P2X1 receptors whose activation leads to eosinophil αMβ2 integrin–dependent adhesion. P2X1 responses are constitutively reduced in asthmatic compared with healthy eosinophils, probably as the result of an increase in extracellular nucleotide concentration

Impaired P2X1 Receptor–Mediated Adhesion in Eosinophils from Asthmatic Patients

Eosinophils play an important role in the pathogenesis of asthma and can be activated by extracellular nucleotides released following cell damage or inflammation. For example, increased ATP concentrations were reported in bronchoalveolar lavage fluids of asthmatic patients. Although eosinophils are known to express several subtypes of P2 receptors for extracellular nucleotides, their function and contribution to asthma remain unclear. In this article, we show that transcripts for P2X1, P2X4, and P2X5 receptors were expressed in healthy and asthmatic eosinophils. The P2X receptor agonist α,β-methylene ATP (α,β-meATP; 10 μM) evoked rapidly activating and desensitizing inward currents (peak 18 ± 3 pA/pF at −60 mV) in healthy eosinophils, typical of P2X1 homomeric receptors, which were abolished by the selective P2X1 antagonist NF449 (1 μM) (3 ± 2 pA/pF). α,β-meATP–evoked currents were smaller in eosinophils from asthmatic patients (8 ± 2 versus 27 ± 5 pA/pF for healthy) but were enhanced following treatment with a high concentration of the nucleotidase apyrase (17 ± 5 pA/pF for 10 IU/ml and 11 ± 3 pA/pF for 0.32 IU/ml), indicating that the channels are partially desensitized by extracellular nucleotides. α,β-meATP (10 μM) increased the expression of CD11b activated form in eosinophils from healthy, but not asthmatic, donors (143 ± 21% and 108 ± 11% of control response, respectively). Furthermore, α,β-meATP increased healthy (18 ± 2% compared with control 10 ± 1%) but not asthmatic (13 ± 1% versus 10 ± 0% for control) eosinophil adhesion. Healthy human eosinophils express functional P2X1 receptors whose activation leads to eosinophil αMβ2 integrin–dependent adhesion. P2X1 responses are constitutively reduced in asthmatic compared with healthy eosinophils, probably as the result of an increase in extracellular nucleotide concentration

Astegolimab, an anti-ST2, in chronic obstructive pulmonary disease - COPD-ST2OP : a phase IIa, placebo-controlled trial

No description supplie

IPA pathway synaptic long term potentiation.

<p>Results of the Ingenuity pathway analysis (IPA) for the pathway “Synaptic Long Term Potentiation” are shown. Shared schizophrenia-bipolar disorder associated genes (<i>GRIN2A</i>, <i>GRM3</i>, <i>CACNA1C</i>) are highlighted in purple.</p

Results of the INRICH pathway analysis.

<p>Results of the INRICH pathway analysis are shown in bar plot format. The x-axis shows negative logarithmic enrichment p-values for all nominally associated pathways containing two and more genes prior to- (gray) and after- (blue) correction for multiple testing. The red horizontal line indicates a p-value of 0.05.</p