PPARs in Alveolar Macrophage Biology

PPARs, most notably PPAR-γ, play a crucial role in regulating the activation of alveolar macrophages, which in turn occupy a pivotal place in the immune response to pathogens and particulates drawn in with inspired air. In this review, we describe the dual role of the alveolar macrophage as both a first-line defender through its phagocytotic activity and a regulator of the immune response. Depending on its state of activation, the alveolar macrophage may either enhance or suppress different aspects of immune function in the lung. We then review the role of PPAR-γ and its ligands in deactivating alveolar macrophages—thus limiting the inflammatory response that, if unchecked, could threaten the essential respiratory function of the alveolus—while upregulating the cell's phagocytotic activity. Finally, we examine the role that inadequate or inappropriate PPAR-γ responses play in specific lung diseases

Why my photos look sideways or upside down? Detecting Canonical Orientation of Images using Convolutional Neural Networks

Image orientation detection requires high-level scene understanding. Humans use object recognition and contextual scene information to correctly orient images. In literature, the problem of image orientation detection is mostly confronted by using low-level vision features, while some approaches incorporate few easily detectable semantic cues to gain minor improvements. The vast amount of semantic content in images makes orientation detection challenging, and therefore there is a large semantic gap between existing methods and human behavior. Also, existing methods in literature report highly discrepant detection rates, which is mainly due to large differences in datasets and limited variety of test images used for evaluation. In this work, for the first time, we leverage the power of deep learning and adapt pre-trained convolutional neural networks using largest training dataset to-date for the image orientation detection task. An extensive evaluation of our model on different public datasets shows that it remarkably generalizes to correctly orient a large set of unconstrained images; it also significantly outperforms the state-of-the-art and achieves accuracy very close to that of humans

Hypermethylation of ribosomal DNA in human breast carcinoma

We examined the methylation status of the transcribed domain of ribosomal DNA (rDNA) in 58 patients with breast cancer. The mean percent of methylation was significantly higher in breast tumours than that of normal control samples (P< 0.0001). This increased rDNA methylation was associated with oestrogen receptor non-expression (P< 0.0273) and with moderately or poorly differentiated tumours as compared to well differentiated tumours (P< 0.0475). Our results suggest that rDNA can be a useful marker for monitoring aberrant methylation during breast tumour progression. © 2000 Cancer Research Campaig

Integrating education into primary care quality and cost improvement at an academic medical center

Introduction: In 1996 the University of Michigan Health System created the Guidelines Utilization, Implementation, Development, and Evaluation Studies (GUIDES) unit to improve the quality and cost-effectiveness of primary care for common medical problems. GUIDES's primary functions are to oversee the development of evidence-based, practical clinical guidelines for common medical conditions; measure and provide feedback on physicians' performance; and facilitate systemic changes to support appropriate care. Various methods are used to improve care, including evidence reviews, formal education, informal clinical “opinion leaders,” feedback, reminders, and procedure changes. Twenty-four common medical conditions have been addressed through this process. More than 30 measures of clinical performance have been developed and reported. Methods: This case study describes a systematic, multifaceted program to improve the quality and cost-effectiveness of primary care. Results: Illustrative results for clinical performance are presented for 2 measures of chronic care, 2 measures of preventive care, and 2 measures of acute care. All 6 measures show general improvement in performance across years, with performance near or above the National Committee for Quality Assurance's 90th percentile for Health Plan Employer Data and Information Set measures. Discussion: A systematic approach involving all relevant components of a health system integrates the synthesis of information, education about the information and how to implement it, and addressing operational barriers. Benefits include a curriculum that is shared across faculty, residents, and medical students and more uniform quality of care that faculty model for physicians-in-training.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/49319/1/80_ftp.pd

Therapeutic Efficacy of Cintredekin Besudotox (IL13-PE38QQR) in Murine Lung Fibrosis Is Unaffected by Immunity to Pseudomonas aeruginosa Exotoxin A

Background: We have previously explored a therapeutic strategy for specifically targeting the profibrotic activity of IL-13 during experimental pulmonary fibrosis using a fusion protein comprised of human IL-13 and a mutated form of Pseudomonas aeruginosa exotoxin A (IL13-PE) and observed that the intranasal delivery of IL13-PE reduced bleomycin-induced pulmonary fibrosis through its elimination of IL-13-responsive cells in the lung. The aim of the present study was to determine whether the presence of an immune response to P. aeruginosa and/or its exotoxin A (PE) would diminish the anti-fibrotic properties of IL13-PE. Methodology/Principal Findings: Fourteen days after P. aeruginosa infection, C57BL/6 mice were injected with bleomycin via the intratracheal route. Other groups of mice received 4 doses of saline or IL13-PE by either intranasal or intraperitoneal application, and were challenged i.t. with bleomycin 28 days later. At day 21 after bleomycin, all mice received either saline vehicle or IL13-PE by the intranasal route and histopatological analyses of whole lung samples were performed at day 28 after bleomycin. Intrapulmonary P. aeruginosa infection promoted a neutralizing IgG2A and IgA antibody response in BALF and serum. Surprisingly, histological analysis showed that a prior P. aeruginosa infection attenuated the development of bleomycin-induced pulmonary fibrosis, which was modestly further attenuated by the intranasal administration of IL13-PE. Although prior intranasal administration of IL13-PE failed to elicit an antibody response, the systemic administration of IL13-PE induced a strong neutralizing antibody response. However, the prior systemic sensitization of mice with IL13-PE did not inhibit the anti-fibrotic effect of IL13-PE in fibrotic mice. Conclusions: Thus, IL13-PE therapy in pulmonary fibrosis works regardless of the presence of a humoral immune response to Pseudomonas exotoxin A. Interestingly, a prior infection with P. aeruginosa markedly attenuated the pulmonary fibrotic response suggesting that the immune elicitation by this pathogen exerts anti-fibrotic effects.National Institutes of Health (NIH)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)NeoPharm, In

Constraining the Nature of Dark Energy using the SKA

We investigate the potential of the Square Kilometer Array Telescope (SKA) to constrain the sound speed of dark energy. The Integrated Sachs Wolfe (ISW) effect results in a significant power spectrum signal when CMB temperature anisotropies are cross-correlated with galaxies detectable with the SKA in HI. We consider using this measurement, the autocorrelation of HI galaxies and the CMB temperature power spectrum to derive constraints on the sound speed. We study the contributions to the cross-correlation signal made by galaxies at different redshifts and use redshift tomography to improve the signal-to-noise. We use a chi-square analysis to estimate the significance of detecting a sound speed different from that expected in quintessence models, finding that there is potential to distinguish very low sound speeds from the quintessence value.Comment: 8 pages, 8 figures; updated references for publication MNRA

Hazard and consequence analysis for waste emplacement at the Waste Isolation Pilot Plant

The Carlsbad Area Office established and analyzed the safety bases for the design and operations as documented in the WIPP Safety Analysis Report (SAR). Additional independent efforts are currently underway to assess the hazards associated with the long-term (10,000 year) isolation period as required by 40 CFR 191. The structure of the WIPP SAR is unique due to the hazards involved, and the agreement between the State of New Mexico and the DOE regarding SAR content and format. However, the hazards and accident analysis philosophy as contained in DOE-STD-3009-94 was followed as closely as possible, while adhering to state agreements. Hazards associated with WIPP waste receipt, emplacement, and disposal operations were systematically identified using a modified Hazard and Operability Study (HAZOP) technique. The WIPP HAZOP assessed the potential internal, external, and natural phenomena events that can cause the identified hazards to develop into accidents. The hazard assessment identified deviations from the intended design and operation of the waste handling system, analyzed potential accident consequences to the public and workers, estimated likelihood of occurrence, and evaluated associated preventative and mitigative features. It was concluded from the assessment that the proposed WIPP waste emplacement operations and design are sufficient to ensure safety of the public, workers, and environment, over the 35 year disposal phase

Protective Role of Interleukin-10 in Ozone-Induced Pulmonary Inflammation

BackgroundThe mechanisms underlying ozone (O3)-induced pulmonary inflammation remain unclear. Interleukin-10 (IL-10) is an anti-inflammatory cytokine that is known to inhibit inflammatory mediators.ObjectivesWe investigated the molecular mechanisms underlying interleuken-10 (IL-10)–mediated attenuation of O3-induced pulmonary inflammation in mice.MethodsIl10-deficient (Il10−/−) and wild-type (Il10+/+) mice were exposed to 0.3 ppm O3 or filtered air for 24, 48, or 72 hr. Immediately after exposure, differential cell counts and total protein (a marker of lung permeability) were assessed from bronchoalveolar lavage fluid (BALF). mRNA and protein levels of cellular mediators were determined from lung homogenates. We also used global mRNA expression analyses of lung tissue with Ingenuity Pathway Analysis to identify patterns of gene expression through which IL-10 modifies O3-induced inflammation.ResultsMean numbers of BALF polymorphonuclear leukocytes (PMNs) were significantly greater in Il10−/− mice than in Il10+/+ mice after exposure to O3 at all time points tested. O3-enhanced nuclear NF-κB translocation was elevated in the lungs of Il10−/− compared with Il10+/+ mice. Gene expression analyses revealed several IL-10–dependent and O3-dependent mediators, including macrophage inflammatory protein 2, cathepsin E, and serum amyloid A3.ConclusionsResults indicate that IL-10 protects against O3-induced pulmonary neutrophilic inflammation and cell proliferation. Moreover, gene expression analyses identified three response pathways and several genetic targets through which IL-10 may modulate the innate and adaptive immune response. These novel mechanisms of protection against the pathogenesis of O3-induced pulmonary inflammation may also provide potential therapeutic targets to protect susceptible individuals

Non-invasive mechanical ventilation for diagnostic bronchoscopy using a new face mask: an observational feasibility study

Contains fulltext : 89809.pdf (publisher's version ) (Closed access)PURPOSE: Bronchoscopy is an indispensable tool for invasive pulmonary evaluation with high diagnostic yield and low incidence of major complications. However, hypoxemia increases the risk of complications, in particular after bronchoalveolar lavage. Non-invasive positive pressure ventilation may prevent hypoxemia associated with bronchoalveolar lavage. The purpose of this study is to present a modified total face mask to aid bronchoscopy during non-invasive positive pressure ventilation. METHODS: A commercially available full face mask was modified to allow introduction of the bronchoscope without interfering with the ventilator circuit. Bronchoscopy with bronchoalveolar lavage was performed in 12 hypoxemic non-ICU patients during non-invasive positive pressure ventilation in the ICU. Results : Patients had severely impaired oxygen uptake as indicated by PaO(2)/FiO(2) ratio 192 +/- 23 mmHg before bronchoscopy. Oxygenation improved after initiation of non-invasive positive pressure ventilation. In all patients the procedure could be completed without subsequent complications, although in one patient SpO(2) decreased until 86% during bronchoscopy. A microbiological diagnosis could be established in 8 of 12 patients with suspected for infection. CONCLUSIONS: Our modified face mask for non-invasive positive pressure ventilation is a valuable tool to aid diagnostic bronchoscopy in hypoxemic patients.1 januari 201