Dealing with Danger in the CNS: The Response of the Immune System to Injury

Fighting pathogens and maintaining tissue homeostasis are prerequisites for survival. Both of these functions are upheld by the immune system, though the latter is often overlooked in the context of the CNS. The mere presence of immune cells in the CNS was long considered a hallmark of pathology, but this view has been recently challenged by studies demonstrating that immunological signaling can confer pivotal neuroprotective effects on the injured CNS. In this review, we describe the temporal sequence of immunological events that follow CNS injury. Beginning with immediate changes at the injury site, including death of neural cells and release of damage-associated molecular patterns (DAMPs), and progressing through innate and adaptive immune responses, we describe the cascade of inflammatory mediators and the implications of their post-injury effects. We conclude by proposing a revised interpretation of immune privilege in the brain, which takes beneficial neuro-immune communications into account

Connecting the Dots: The Promise of Integrated Data Systems for Policy Analysis and Systems Reform

This article explores the use of integrated administrative data systems in support of policy reform through interagency collaboration and research. The legal, ethical, scientific and economic challenges of interagency data sharing are examined. A survey of eight integrated data systems, including states, local governments and university-based efforts, explores how the developers have addressed these challenges. Some exemplary uses of the systems are provided to illustrate the range, usefulness and import of these systems for policy and program reform. Recommendations are offered for the broader adoption of these systems and for their expanded use by various stakeholders

RIPK3-Dependent Recruitment of Low-Inflammatory Myeloid Cells Does Not Protect from Systemic Salmonella Infection

ABSTRACT Regulated macrophage death has emerged as an important mechanism to defend against intracellular pathogens. However, the importance and consequences of macrophage death during bacterial infection are poorly resolved. This is especially true for the recently described RIPK3-dependent lytic cell death, termed necroptosis. Salmonella enterica serovar Typhimurium is an intracellular pathogen that precisely regulates virulence expression within macrophages to evade and manipulate immune responses, which is a key factor in its ability to cause severe systemic infections. We combined genetic and pharmacological approaches to examine the importance of RIPK3 for S. Typhimurium-induced macrophage death using conditions that recapitulate bacterial gene expression during systemic infection in vivo. Our findings indicate that noninvasive S. Typhimurium does not naturally induce macrophage necroptosis but does so in the presence of pan-caspase inhibition. Moreover, our data suggest that RIPK3 induction (following caspase inhibition) does not impact host survival following S. Typhimurium infection, which differs from previous findings based on inert lipopolysaccharide (LPS) injections. Finally, although necroptosis is typically characterized as highly inflammatory, our data suggest that RIPK3 skews the peritoneal myeloid population away from an inflammatory profile to that of a classically noninflammatory profile. Collectively, these data improve our understanding of S. Typhimurium-macrophage interactions, highlight the possibility that purified bacterial components may not accurately recapitulate the complexity of host-pathogen interactions, and reveal a potential and unexpected role for RIPK3 in resolving inflammation. IMPORTANCE Macrophages employ multiple strategies to limit pathogen infection. For example, macrophages may undergo regulated cell death, including RIPK3-dependent necroptosis, as a means of combatting intracellular bacterial pathogens. However, bacteria have evolved mechanisms to evade or exploit immune responses. Salmonella is an intracellular pathogen that avoids and manipulates immune detection within macrophages. We examined the contribution of RIPK3 to Salmonella-induced macrophage death. Our findings indicate that noninvasive Salmonella does not naturally induce necroptosis, but it does so when caspases are inhibited. Moreover, RIPK3 induction (following caspase inhibition) does not impact host survival following Salmonella systemic infection. Finally, our data show that RIPK3 induction results in recruitment of low-inflammatory myeloid cells, which was unexpected, as necroptosis is typically described as highly inflammatory. Collectively, these data improve our understanding of pathogen-macrophage interactions, including outcomes of regulated cell death during infection in vivo, and reveal a potential new role for RIPK3 in resolving inflammation

The Ursinus Weekly, April 27, 1953

Y to sponsor panel meeting with Albright • Price, Merrifield, Haines, Hartman to head WSGA, WAA, YWCA, YMCA • May Day dancers prepare pageant for gala weekend • Concert presented by Meistersingers • Fraternities plan May dinner dances • Sororities make plans for shore visits, dinner dances • Group plays to be given • Eight win full scholarships • French teachers\u27 conference held at Ursinus, April 25 • Thespians to give Two blind mice • Friedlin crowned queen; Cub & Key honors five • Radomski, Wong elected to pre-med society offices • Class and council petitioning ends Friday • Jones reads from works of Noyes and Lindsay on Tuesday • Editorials: Tradition vs. common sense • I love Spring! • Helfferich named to board • Career offer for grads • Letters to the editor • Are you wasting money? • Alumni news • U.C. co-ed gives inside scoop on life in a boys\u27 dormitory • Ursinus professors are authorities in subject fields • From memoirs of a freshman: A visit to the Supply Store • Bears drop track meet to West Chester, 69-57 • Bryn Mawr tops girls in tennis • Baseball team loses, 8-7; But tops Graterford, 7-3 • East Stroudsburg routs Belles, 5-0 • Men\u27s tennis team loses, 5-4 • Belles, Albright vie in softball opener • Court squad downs Chestnut Hill, 5-0 • Hutch twirls shut-out; Bears beat Pharmacy, 20-0https://digitalcommons.ursinus.edu/weekly/1518/thumbnail.jp

Serum Amyloid A Facilitates Early Lesion Development in \u3cem\u3eLdlr\u3csup\u3e-/-\u3c/sup\u3e\u3c/em\u3e Mice

BACKGROUND: Atherosclerosis is a chronic inflammatory disorder, and several studies have demonstrated a positive association between plasma serum amyloid A (SAA) levels and cardiovascular disease risk. The aim of the study was to examine whether SAA has a role in atherogenesis, the underlying basis of most cardiovascular disease. METHODS AND RESULTS: Mice globally deficient in acute-phase isoforms Saa1 and Saa2 (Saa-/-) were crossed to Ldlr-/- mice (Saa-/-Ldlr-/-). Saa-/-Ldlr-/- mice demonstrated a 31% reduction in lesional area in the ascending aorta but not in the aortic root or innominate artery after consuming a high-fat, high-cholesterol Western-type diet for 6 weeks. The lesions were predominantly macrophage foam cells. The phenotype was lost in more mature lesions in mice fed a Western-type diet for 12 weeks, suggesting that SAA is involved in early lesion development. The decreased atherosclerosis in the Saa-/-Ldlr-/- mice occurred despite increased levels of blood monocytes and was independent of plasma lipid levels. SAA is produced predominantly by hepatocytes and macrophages. To determine which source of SAA may have a dominant role in lesion development, bone marrow transplantation was performed. Ldlr-/- mice that received bone marrow from Saa-/-Ldlr-/- mice had slightly reduced ascending aorta atherosclerosis compared with Saa-/-Ldlr-/- mice receiving bone marrow from Ldlr-/- mice, indicating that the expression of SAA by macrophages may have an important influence on atherogenesis. CONCLUSIONS: The results indicate that SAA produced by macrophages promotes early lesion formation in the ascending aorta

A Model-Based Approach to Predict Short-Term Toxicity Benefits With Proton Therapy for Oropharyngeal Cancer

Purpose: The aim of this study was to generate normal tissue complication probability (NTCP) models in patients treated with either proton beam therapy (PBT) or intensitymodulated radiation therapy (IMRT) for oropharynx cancer and to use a model-based approach to investigate the added value of PBT in preventing treatment complications. Methods and Materials: For patients with advanced-stage oropharynx cancer treated with curative intent (PBT, n = 30; IMRT, n = 175), NTCP models were developed using multivariable logistic regression analysis with backward selection. For PBTtreated patients, an equivalent IMRT plan was generated to serve as a reference to determine the benefit of PBT in terms of NTCP. The models were then applied to the PBT-treated patients to compare predicted and observed clinical outcomes (calibration- in-the-large). Five binary endpoints were analyzed at 6 months after treatment: dysphagia >= grade 2, dysphagia >= grade 3, xerostomia >= grade 2, salivary duct inflammation >= grade 2, and feeding tube dependence. Corresponding toxicity grading was based on National Cancer Institute Common Terminology Criteria for Adverse Events version 4. Paired t tests and Wilcoxon rank tests were used to compare mean NTCP results for endpoints between PBT and IMRT. Results: NTCP models developed based on outcomes from all patients were applied to those receiving PBT. NTCP values were calculated for the equivalent IMRT plans for all PBT-treated patients, revealing significantly higher NTCP values with IMRT. PBT was associated with statistically significant reductions in the mean NTCP values for each endpoint at 6 months after treatment, with the largest absolute differences in rates of >= grade 2 dysphagia and >= grade 2 xerostomia. Conclusions: NTCP models predict significant improvements in the probability of short-term, treatment-related toxicity with PBT compared with IMRT for oropharyngeal cancer. This study demonstrates an NTCP model-based approach to compare predicted patient outcomes when randomized data are not available. (C) 2019 Elsevier Inc. All rights reserved

The Ursinus Weekly, May 12, 1952

WSGA to install officers at banquet on Thursday • Sororities hold dances, elections • Ruby selects photographer • College physician, famous coach, dies • WAA gives banquet • Bus. Ad. club takes poll • Queen and court reign at May Day pageant • Commencement, Baccalaureate speakers announced • Rosicrucians to entertain new members • Curtain Club, Alpha Psi elect new presidents • Four fraternities pick new officers • Voegler to speak at Pottstown • Campus groups hold annual elections: IRC, FTA, French Club • Queen to be on TV • Editorials: Good idea; Class struggle; Capitalistic noise and smoke • Class of 1952 is invited to Alumni Association dinner • Phila. Story is grand success • Alumni group plans banquet • Pinned • Ursinus routs Pharmacy with twenty run splurge • Snell\u27s Belles win in opener • Feist hurls five hitter, Bears rout Drexel, 9-4 • Physics Department develops film loops for better teaching • Famous columnist and editor speaks to FTA • Plans of \u2752 graduates reveal varied interests • Elizabethtown wins with eight run inning, 10 to 3 • Belles trounce West Chester • Men\u27s tennis squad victor • JV softball team whips Drexel 8-3 • Ursinus cinder men lose close meet to Albright • Ursinus finishes second in track • Y plans hot dog roast for May 14 • Marine representative speaks • Engagement • Marriagehttps://digitalcommons.ursinus.edu/weekly/1544/thumbnail.jp