Microarray analysis of mouse ling examining the augmented pseudomonas aeruginosa clearance following mild traumatic brain injury

Our murine model of mild traumatic brain injury (mTBI) has shown improved survival after Pseudomonas aeruginosa (Psd) challenge as compared to controls (tail trauma or sham injury). Previous work suggests an mTBI-specific involvement of the neuro-immune axis which augments the innate immune response, increasing survival. Additional factors for the enhanced mTBI survival were explored via microarray analysis of lungs harvested 48 hours post-trauma, the point prior to Psd challenge in our model. At 48 hours post-trauma, mTBI lungs have a number of upregulated ATP synthesis and mitochondrial gene sets. Increased available energy could prime the mTBI lungs, allowing an earlier and more robust response to Psd infection, possibly contributing to the increased mTBI survival. This is supported by increased neutrophil recruitment in the bronchoalveolar lavage of mTBI mice four hours after Psd instillation. Downregulated gene sets related to cellular connections suggest that neutrophils recruited to the lung have an easier extravasation pathway into the air space of mTBI lungs compared to control. Based on genetic and neutrophil recruitment data, it is possible that mTBI creates an energetically prepared and easily accessible lung better tailored for recruiting and allowing entry of neutrophils in response to an infection compared to control

Reducing LPS content in cockroach allergens increases pulmonary cytokine production without increasing inflammation: A randomized laboratory study

<p>Abstract</p> <p>Background</p> <p>Endotoxins are ubiquitously present in the environment and constitute a significant component of ambient air. These substances have been shown to modulate the allergic response, however a consensus has yet to be reached whether they attenuate or exacerbate asthmatic responses. The current investigation examined whether reducing the concentration of lipopolysaccharide (LPS) in a house dust extract (HDE) containing high concentrations of both cockroach allergens <abbrgrp><abbr bid="B1">1</abbr></abbrgrp> and LPS would attenuate asthma-like pulmonary inflammation.</p> <p>Methods</p> <p>Mice were sensitized with CRA and challenged with the intact HDE, containing 182 ng of LPS, or an LPS-reduced HDE containing 3 ng LPS, but an equivalent amount of CRA. Multiple parameters of asthma-like pulmonary inflammation were measured.</p> <p>Results</p> <p>Compared to HDE challenged mice, the LPS-reduced HDE challenged mice had significantly reduced TNFα levels in the bronchoalveolar lavage fluid. Plasma levels of IgE and IgG1 were significantly reduced, however no change in CRA-specific IgE was detected. In HDE mice, plasma IgG2a levels were similar to naïve mice, while LPS-reduced HDE mice had significantly greater concentrations. Reduced levels of LPS in the HDE did not decrease eosinophil or neutrophil recruitment into the alveolar space. Equivalent inflammatory cell recruitment occurred despite having generally higher pulmonary concentrations of eotaxins and CXC chemokines in the LPS-reduced HDE group. LPS-reduced HDE challenge induced significantly higher concentrations of IFNγ, and IL-5 and IL-13 in the BAL fluid, but did not decrease airways hyperresponsiveness or airway resistance to methacholine challenge. <it>Conclusion: </it>These data show that reduction of LPS levels in the HDE does not significantly protect against the severity of asthma-like pulmonary inflammation.</p

Evaluation of a Deep Neural Network for Automated Classification of Colorectal Polyps on Histopathologic Slides

Importance: Histologic classification of colorectal polyps plays a critical role in screening for colorectal cancer and care of affected patients. An accurate and automated algorithm for the classification of colorectal polyps on digitized histopathologic slides could benefit practitioners and patients. Objective: To evaluate the performance and generalizability of a deep neural network for colorectal polyp classification on histopathologic slide images using a multi-institutional data set. Design, Setting, and Participants: This prognostic study used histopathologic slides collected from January 1, 2016, to June 31, 2016, from Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, with 326 slides used for training, 157 slides for an internal data set, and 25 for a validation set. For the external data set, 238 slides for 179 distinct patients were obtained from 24 institutions across 13 US states. Data analysis was performed from April 9 to November 23, 2019. Main Outcomes and Measures: Accuracy, sensitivity, and specificity of the model to classify 4 major colorectal polyp types: tubular adenoma, tubulovillous or villous adenoma, hyperplastic polyp, and sessile serrated adenoma. Performance was compared with that of local pathologists' at the point of care identified from corresponding pathology laboratories. Results: For the internal evaluation on the 157 slides with ground truth labels from 5 pathologists, the deep neural network had a mean accuracy of 93.5% (95% CI, 89.6%-97.4%) compared with local pathologists' accuracy of 91.4% (95% CI, 87.0%-95.8%). On the external test set of 238 slides with ground truth labels from 5 pathologists, the deep neural network achieved an accuracy of 87.0% (95% CI, 82.7%-91.3%), which was comparable with local pathologists' accuracy of 86.6% (95% CI, 82.3%-90.9%). Conclusions and Relevance: The findings suggest that this model may assist pathologists by improving the diagnostic efficiency, reproducibility, and accuracy of colorectal cancer screenings

A Novel Compound C12 Inhibits Inflammatory Cytokine Production and Protects from Inflammatory Injury In Vivo

Inflammation is a hallmark of many diseases. Although steroids and cyclooxygenase inhibitors are main anti-inflammatory therapeutical agents, they may cause serious side effects. Therefore, developing non-steroid anti-inflammatory agents is urgently needed. A novel hydrosoluble compound, C12 (2,6-bis(4-(3-(dimethylamino)-propoxy)benzylidene)cyclohexanone), has been designed and synthesized as an anti-inflammatory agent in our previous study. In the present study, we investigated whether C12 can affect inflammatory processes in vitro and in vivo. In mouse primary peritoneal macrophages, C12 potently inhibited the production of the proinflammatory gene expression including TNF-α, IL-1β, IL-6, iNOS, COX-2 and PGE synthase. The activity of C12 was partly dependent on inhibition of ERK/JNK (but p38) phosphorylation and NF-κB activation. In vivo, C12 suppressed proinflammatory cytokine production in plasma and liver, attenuated lung histopathology, and significantly reduced mortality in endotoxemic mice. In addition, the pre-treatment with C12 reduced the inflammatory pain in the acetic acid and formalin models and reduced the carrageenan-induced paw oedema and acetic acid-increased vascular permeability. Taken together, C12 has multiple anti-inflammatory effects. These findings, coupled with the low toxicity and hydrosolubility of C12, suggests that this agent may be useful in the treatment of inflammatory diseases