Oxidized Low-Density Lipoprotein Immune Complex Priming of the Nlrp3 Inflammasome Involves TLR and Fc{gamma}R Cooperation and Is Dependent on CARD9 [INNATE IMMUNITY AND INFLAMMATION]

Oxidized low-density lipoprotein (oxLDL) is known to activate inflammatory responses in a variety of cells, especially macrophages and dendritic cells. Interestingly, much of the oxLDL in circulation is complexed to Abs, and these resulting immune complexes (ICs) are a prominent feature of chronic inflammatory disease, such as atherosclerosis, type-2 diabetes, systemic lupus erythematosus, and rheumatoid arthritis. Levels of oxLDL ICs often correlate with disease severity, and studies demonstrated that oxLDL ICs elicit potent inflammatory responses in macrophages. In this article, we show that bone marrow–derived dendritic cells (BMDCs) incubated with oxLDL ICs for 24 h secrete significantly more IL-1β compared with BMDCs treated with free oxLDL, whereas there was no difference in levels of TNF-α or IL-6. Treatment of BMDCs with oxLDL ICs increased expression of inflammasome-related genes Il1a, Il1b, and Nlrp3, and pretreatment with a caspase 1 inhibitor decreased IL-1β secretion in response to oxLDL ICs. This inflammasome priming was due to oxLDL IC signaling via multiple receptors, because inhibition of CD36, TLR4, and FcR significantly decreased IL-1β secretion in response to oxLDL ICs. Signaling through these receptors converged on the adaptor protein CARD9, a component of the CARD9–Bcl10–MALT1 signalosome complex involved in NF-B translocation. Finally, oxLDL IC–mediated IL-1β production resulted in increased Th17 polarization and cytokine secretion. Collectively, these data demonstrate that oxLDL ICs induce inflammasome activation through a separate and more robust mechanism than oxLDL alone and that these ICs may be immunomodulatory in chronic disease and not just biomarkers of severity.

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Cathepsin K Deficiency Ameliorates Systemic Lupus Erythematosus-like Manifestations in Faslpr Mice [AUTOIMMUNITY]

Cysteinyl cathepsin K (CatK) is expressed in osteoclasts to mediate bone resorption, but is also inducible under inflammatory conditions. Fas^lpr mice on a C57BL/6 background develop spontaneous systemic lupus erythematosus-like manifestations. Although normal mouse kidneys expressed negligible CatK, those from Fas^lpr mice showed elevated CatK expression in the glomeruli and tubulointerstitial space. Fas^lpr mice also showed elevated serum CatK levels. CatK deficiency in Fas^lpr mice reduced all tested kidney pathologies, including glomerulus and tubulointerstitial scores, glomerulus complement C3 and IgG deposition, chemokine expression and macrophage infiltration, and serum autoantibodies. CatK contributed to Fas^lpr mouse autoimmunity and pathology in part by its activity in TLR-7 proteolytic processing and consequent regulatory T (Treg) cell biology. Elevated TLR7 expression and proteolytic processing in Fas^lpr mouse kidneys and Tregs showed significantly reduced levels in CatK-deficient mice, leading to increased spleen and kidney Treg content. Purified CD4⁺CD25^highFoxp3⁺ Tregs from CatK-deficient mice doubled their immunosuppressive activity against T effector cells, compared with those from CatK-sufficient mice. In Fas^lpr mice, repopulation of purified Tregs from CatK-sufficient mice reduced spleen sizes, autoantibody titers, and glomerulus C3 and IgG deposition, and increased splenic and kidney Treg contents. Tregs from CatK-deficient mice had significantly more potency than CatK-sufficient Tregs in reducing spleen sizes, serum autoantibody titers, and glomerulus C3 deposition, and in increasing splenic and kidney Treg content. This study established a possible role of CatK in TLR7 proteolytic activation, Treg immunosuppressive activity, and lupus autoimmunity and pathology.

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Forward Masking in Cochlear Implant Users: Electrophysiological and Psychophysical Data Using Pulse Train Maskers

Abstract

Electrical stimulation of auditory nerve fibers using cochlear implants (CI) shows psychophysical forward masking (pFM) up to several hundreds of milliseconds. By contrast, recovery of electrically evoked compound action potentials (eCAPs) from forward masking (eFM) was shown to be more rapid, with time constants no greater than a few milliseconds. These discrepancies suggested two main contributors to pFM: a rapid-recovery process due to refractory properties of the auditory nerve and a slow-recovery process arising from more central structures. In the present study, we investigate whether the use of different maskers between eCAP and psychophysical measures, specifically single-pulse versus pulse train maskers, may have been a source of confound.

In experiment 1, we measured eFM using the following: a single-pulse masker, a 300-ms low-rate pulse train masker (LTM, 250 pps), and a 300-ms high-rate pulse train masker (HTM, 5000 pps). The maskers were presented either at same physical current (Φ) or at same perceptual (Ψ) level corresponding to comfortable loudness. Responses to a single-pulse probe were measured for masker-probe intervals ranging from 1 to 512 ms. Recovery from masking was much slower for pulse trains than for the single-pulse masker. When presented at Φ level, HTM produced more and longer-lasting masking than LTM. However, results were inconsistent when LTM and HTM were compared at Ψ level. In experiment 2, masked detection thresholds of single-pulse probes were measured using the same pulse train masker conditions. In line with our eFM findings, masked thresholds for HTM were higher than those for LTM at Φ level. However, the opposite result was found when the pulse trains were presented at Ψ level.

Our results confirm the presence of slow-recovery phenomena at the level of the auditory nerve in CI users, as previously shown in animal studies. Inconsistencies between eFM and pFM results, despite using the same masking conditions, further underline the importance of comparing electrophysiological and psychophysical measures with identical stimulation paradigms.

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Emerging Technologies: Let's Not Jump the Gun.

No abstract available

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Pathogenic Link Between Postextubation Pneumonia and Ventilator-Associated Pneumonia: An Experimental Study.

BACKGROUND: The presence of an endotracheal tube is the main cause for developing ventilator-associated pneumonia (VAP), but pneumonia can still develop in hospitalized patients after endotracheal tube removal (postextubation pneumonia [PEP]). We hypothesized that short-term intubation (24 hours) can play a role in the pathogenesis of PEP. To test such hypothesis, we initially evaluated the occurrence of lung colonization and VAP in sheep that were intubated and mechanically ventilated for 24 hours. Subsequently, we assessed the incidence of lung colonization and PEP at 48 hours after extubation in sheep previously ventilated for 24 hours. METHODS: To simulate intubated intensive care unit patients placed in semirecumbent position, 14 sheep were intubated and mechanically ventilated with the head elevated 30[degrees] above horizontal. Seven of them were euthanized after 24 hours (Control Group), whereas the remaining were euthanized after being awaken, extubated, and left spontaneously breathing for 48 hours after extubation (Awake Group). Criteria of clinical diagnosis of pneumonia were tested. Microbiological evaluation was performed on autopsy in all sheep. RESULTS: Only 1 sheep in the Control Group met the criteria of VAP after 24 hours of mechanical ventilation. However, heavy pathogenic bacteria colonization of trachea, bronchi, and lungs (range, 104-109 colony-forming unit [CFU]/g) was reported in 4 of 7 sheep (57%). In the Awake Group, 1 sheep was diagnosed with VAP and 3 developed PEP within 48 hours after extubation (42%), with 1 euthanized at 30 hours because of respiratory failure. On autopsy, 5 sheep (71%) confirmed pathogenic bacterial growth in the lower respiratory tract (range, 103-109 CFU/g). CONCLUSIONS: Twenty-four hours of intubation and mechanical ventilation in semirecumbent position leads to significant pathogenic colonization of the lower airways, which can promote the development of PEP. Strategies directed to prevent pathogenic microbiological colonization before and after mechanical ventilation should be considered to avert the onset of PEP. (C) 2017 International Anesthesia Research Society

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Influence of Fraction of Inspired Oxygen on Noninvasive Hemoglobin Measurement: Parallel Assessment of 2 Monitors.

BACKGROUND: Previous reports have brought specific attention to the relationship between oxygenation of the patient and the accuracy of noninvasive measurement of hemoglobin (Hb) using an optical sensor. This study aimed to assess prospectively the relationship between fraction of inspired oxygen (FIO2) and the bias of the measurement of Hb by the use of 2 different noninvasive monitors compared with the classic invasive technique. METHODS: Forty-four patients were included prospectively. In each individual, Hb level was determined noninvasively by monitor Pronto-7(TM) (Masimo Corporation, Irvine, CA) and by monitor NBM-200MP(TM) (OrSense Ltd, Petah-Tikva, Israel), with the probe placed on 2 fingers on the same hand of the patient. Three measures were performed, first under breathing air and 2 others when fraction of expired oxygen rose to 50% +/- 5% and to 90 +/- 5%. Simultaneously, a nurse collected a venous blood sample, which was sent immediately to the hematology laboratory for Hb measurement. The main outcome measurement was the mean bias between noninvasive and invasive measurements. RESULTS: Results show no change in median bias [interquartile range] with FIO2 for Pronto-7 (from 1.1 g/dL [0.0-2.0] in FIO2 21% to 1.0 g/dL [0.2-1.5] in FIO2 100%), but increasingly negative median bias with increasing FIO2 for NBM-200MP (from -0.3 g/dL [-1.3 to 0.3] in FIO2 21% to -0.8 g/dL [-1.5 to -0.1] in FIO2 100%, P = .04). DISCUSSION: This study showed that noninvasive measurement of Hb could be influenced by inspired fraction of oxygen when the monitor NBM-200MP is used. (C) 2017 International Anesthesia Research Society

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Arginine Therapy Shows Promise for Treatment of Sickle Cell Disease Clinical Subphenotypes of Hemolysis and Arginine Deficiency.

No abstract available

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