The effects of central cholecystokinin receptor blockade on hypothalamic-pituitary-adrenal and symptomatic responses to overnight withdrawal from alprazolam

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142739/1/Abelson-Nesse-alprazolam-BioPsych-1995.pd

Modulation of NRF2/KEAP1 Signaling in Preeclampsia

Placentation is a key and tightly regulated process that ensures the normal development of the placenta and fetal growth. Preeclampsia (PE) is a hypertensive pregnancy-related disorder involving about 5–8% of all pregnancies and clinically characterized by de novo maternal hypertension and proteinuria. In addition, PE pregnancies are also characterized by increased oxidative stress and inflammation. The NRF2/KEAP1 signaling pathway plays an important role in protecting cells against oxidative damage due to increased reactive oxygen species (ROS) levels. ROS activate NRF2, allowing its binding to the antioxidant response element (ARE) region present in the promoter of several antioxidant genes such as heme oxygenase, catalase, glutathione peroxidase and superoxide dismutase that neutralize ROS, protecting cells against oxidative stress damages. In this review, we analyze the current literature regarding the role of the NRF2/KEAP1 pathway in preeclamptic pregnancies, discussing the main cellular modulators of this pathway. Moreover, we also discuss the main natural and synthetic compounds that can regulate this pathway in in vivo and in vitro models

Faculty Evaluation of Student Portfolio Presentations of a Seven-Week Clinical Competency-Based Curriculum Pilot

Background: Student portfolios intend to capture qualitative aspects of students' learning experiences, and foster personal responsibility for learning. However, obtaining standardized assessments of portfolios is challenging. This challenge must be met for a true competency-based curriculum in which students have individualized learning paths and educational goals. Summary of Work: During a six-week pilot of a flexible, competency-based curriculum, 5 students summarized their learning experiences for 7 faculty raters who rated each using a novel 5-item instrument. Presentations were 20 minutes long followed by a 10 minute question period. Follow up ratings of videotaped presentations were used to resolve rater disagreements and improve the rating form. Summary of Results: There was low inter-rater reliability of the rating instrument (item intra-class correlations (ICC) ranged from .00 to .91). Follow-up ratings found agreement easier to reach with better-defined item anchors. Conclusions: The difficulties underlying summative assessment of an inherently qualitative experience are likely surmountable. Allowing students to defend their academic progress to a faculty panel in person is enjoyable and worthwhile. Further refinement of a rating instrument will likely overcome interrater reliability issues. Take home messages: Standardized global performance assessment of individualized learning paths is feasible using faculty ratings of semi-structured student presentations.http://deepblue.lib.umich.edu/bitstream/2027.42/76026/1/stansfield02.dochttp://deepblue.lib.umich.edu/bitstream/2027.42/76026/4/stansfield02.pd

The anaphylatoxins C3a and C5a are vasodilators in the canine coronary vasculature in vitro and in vivo

The effect of complement fragments on coronary blood flow in vivo and the contraction of coronary arteries in vitro was determined. In pentobarbital anesthetized dogs, intraarterial bolus injection of C3a and C5a, zymosan-activated serum and methylcholine in the coronary vascular bed caused transient and dose-dependent increases in coronary blood flow. Similar increases were obtained with 25 μg of C3a (104±13%, n =5) and 0.1 μg of methylcholine (102±4%, n =3). Smaller, increases in blood flow were elicited by 25 μg of C5a (41±18%, n =4) and 0.2 ml, of zymosan-activated serum (48±5%, n =4). None of these responses were associated, with significant changes in left ventricular contractile force measured with a strain gauge, arterial blood pressure, and heart rate. C3a dilated the coronary vascular bed in conscious dogs with an activity equal to or greater than that observed in anesthetized dogs. Isolated canine coronary arteries that were precontracted with serotonin relaxed in response to C3a, whether or not the endothelium was intact. Overall these data suggest that physiologically high doses of anaphylactic complement fragments vasodilate the canine coronary circulation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45056/1/11_2005_Article_BF01988727.pd

Oxygen Radicals and Arachidonate Metabolites in Lung Injury a

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72476/1/j.1749-6632.1986.tb18477.x.pd

TRPA1 Contributes to the Acute Inflammatory Response and Mediates Carrageenan-Induced Paw Edema in the Mouse

Transient receptor potential ankyrin 1 (TRPA1) is an ion channel involved in thermosensation and nociception. TRPA1 is activated by exogenous irritants and also by oxidants formed in inflammatory reactions. However, our understanding of its role in inflammation is limited. Here, we tested the hypothesis that TRPA1 is involved in acute inflammatory edema. The TRPA1 agonist allyl isothiocyanate (AITC) induced inflammatory edema when injected intraplantarly to mice, mimicking the classical response to carrageenan. Interestingly, the TRPA1 antagonist HC-030031 and the cyclo-oxygenase (COX) inhibitor ibuprofen inhibited not only AITC but also carrageenan-induced edema. TRPA1-deficient mice displayed attenuated responses to carrageenan and AITC. Furthermore, AITC enhanced COX-2 expression in HEK293 cells transfected with human TRPA1, a response that was reversed by HC-030031. This study demonstrates a hitherto unknown role of TRPA1 in carrageenan-induced inflammatory edema. The results also strongly suggest that TRPA1 contributes, in a COX-dependent manner, to the development of acute inflammation

Impact of Anti-Inflammatory Agents on the Gene Expression Profile of Stimulated Human Neutrophils: Unraveling Endogenous Resolution Pathways

Adenosine, prostaglandin E2, or increased intracellular cyclic AMP concentration each elicit potent anti-inflammatory events in human neutrophils by inhibiting functions such as phagocytosis, superoxide production, adhesion and cytokine release. However, the endogenous molecular pathways mediating these actions are poorly understood. In the present study, we examined their impact on the gene expression profile of stimulated neutrophils. Purified blood neutrophils from healthy donors were stimulated with a cocktail of inflammatory agonists in the presence of at least one of the following anti-inflammatory agents: adenosine A2A receptor agonist CGS 21680, prostaglandin E2, cyclic-AMP-elevating compounds forskolin and RO 20-1724. Total RNA was analyzed using gene chips and real-time PCR. Genes encoding transcription factors, enzymes and regulatory proteins, as well as secreted cytokines/chemokines showed differential expression. We identified 15 genes for which the anti-inflammatory agents altered mRNA levels. The agents affected the expression profile in remarkably similar fashion, suggesting a central mechanism limiting cell activation. We have identified a set of genes that may be part of important resolution pathways that interfere with cell activation. Identification of these pathways will improve understanding of the capacity of tissues to terminate inflammatory responses and contribute to the development of therapeutic strategies based on endogenous resolution

IL-17A Expression Is Localised to Both Mononuclear and Polymorphonuclear Synovial Cell Infiltrates

This study examines the expression of IL-17A-secreting cells within the inflamed synovium and the relationship to in vivo joint hypoxia measurements.IL-17A expression was quantified in synovial tissue (ST), serum and synovial fluid (SF) by immunohistochemistry and MSD-plex assays. IL-6 SF and serum levels were measured by MSD-plex assays. Dual immunofluorescence for IL-17A was quantified in ST CD15+ cells (neutrophils), Tryptase+ (mast cells) and CD4+ (T cells). Synovial tissue oxygen (tpO(2)) levels were measured under direct visualisation at arthroscopy. Synovial infiltration was assessed using immunohistochemistry for cell specific markers. Peripheral blood mononuclear and polymorphonuclear cells were isolated and exposed to normoxic or 3% hypoxic conditions. IL-17A and IL-6 were quantified as above in culture supernatants.IL-17A expression was localised to mononuclear and polymorphonuclear (PMN) cells in inflamed ST. Dual immunoflourescent staining co-localised IL-17A expression with CD15+ neutrophils Tryptase+ mast cells and CD4+T cells. % IL-17A positivity was highest on CD15+ neutrophils, followed by mast cells and then CD4+T-cells. The number of IL-17A-secreting PMN cells significantly correlated with sublining CD68 expression (r = 0.618, p<0.01). IL-17A SF levels correlated with IL-6 SF levels (r = 0.675, p<0.01). Patients categorized according to tp0(2)< or >20 mmHg, showed those with low tp0(2)<20 mmHg had significantly higher IL-17A+ mononuclear cells with no difference observed for PMNs. Exposure of mononuclear and polymorphonuclear cells to 3% hypoxia, significantly induced IL-6 in mononuclear cells, but had no effect on IL-17A expression in mononuclear and polymorphonuclear cells.This study demonstrates IL-17A expression is localised to several immune cell subtypes within the inflamed synovial tissue, further supporting the concept that IL-17A is a key mediator in inflammatory arthritis. The association of hypoxia with Il-17A expression appears to be indirect, probably through hypoxia-induced pro-inflammatory pathways and leukocyte influx within the joint microenvironment