Urokinase-type plasminogen activator and arthritis progression: contrasting roles in systemic and monoarticular arthritis models

INTRODUCTION: Urokinase-type plasminogen activator (u-PA) has been implicated in tissue destruction/remodeling. The absence of u-PA results in resistance of mice to systemic immune complex-driven arthritis models; monoarticular arthritis models involving an intra-articular (i.a.) antigen injection, on the other hand, develop more severe arthritis in its absence. The aims of the current study are to investigate further these contrasting roles that u-PA can play in the pathogenesis of inflammatory arthritis and to determine whether u-PA is required for the cartilage and bone destruction associated with disease progression. METHODS: To determine how the different pathogenic mechanisms leading to arthritis development in the different models may explain the contrasting requirement for u-PA, the systemic, polyarticular, immune complex-driven K/BxN arthritis model was modified to include an i.a. injection of saline as a local trauma in u-PA-/- mice. This modified model and the antigen-induced arthritis (AIA) model were also used in u-PA-/- mice to determine the requirement for u-PA in joint destruction. Disease severity was determined by clinical and histologic scoring. Fibrin(ogen) staining and the matrix metalloproteinase (MMP)-generated neoepitope DIPEN staining were performed by immunohistochemistry. Gene expression of inflammatory and destructive mediators was measured in joint tissue by quantitative PCR. RESULTS: In our modified arthritis model, u-PA-/- mice went from being resistant to arthritis development following K/BxN serum transfer to being susceptible following the addition of an i.a. injection of saline. u-PA-/- mice also developed more sustained AIA compared with C57BL/6 mice, including reduced proteoglycan levels and increased bone erosions, fibrin(ogen) deposition and DIPEN expression. Synovial gene expression of the proinflammatory mediators (TNF and IL-1β), aggrecanases (ADAMTS-4 and -5) and MMPs (MMP3 and MMP13) were all sustained over time following AIA induction in u-PA-/- mice compared with C57BL/6 mice. CONCLUSIONS: We propose that u-PA has a protective role in arthritis models with 'wound healing-like' processes following local trauma, possibly through u-PA/plasmin-mediated fibrinolysis, but a deleterious role in systemic models that are critically dependent on immune complex formation and complement activation. Given that cartilage proteoglycan loss and bone erosions were present and sustained in u-PA-/- mice with monoarticular arthritis, it is unlikely that u-PA/plasmin-mediated proteolysis is contributing directly to this tissue destruction/remodeling

Sediment supply and barrier dynamics as driving mechanisms of Holocene coastal change for the southern North Sea basin

The combined effects of climate change and human impact lead to regional and local coastal responses that pose major challenges for the future resilience of coastal landscapes, increasing the vulnerability of communities, infrastructure and nature conservation interests. Using the Suffolk coast, southeast England, as a case study, we investigate the importance of sediment supply and barrier dynamics as driving mechanisms of coastal change throughout the Holocene. Litho-, bio- and chronostratigraphic methods are used to decipher the mechanisms of coastal change from the record preserved within coastal stratigraphy. Results suggest that local coastal configuration and sediment supply were the most influential in determining coastal change during the mid- and late Holocene, against a background control of sea-level rise. The importance of sedimentological and morphological factors in shaping Holocene coastal changes in the southern North Sea basin must therefore be considered when using the database of evidence from this region as an analogue for future change under accelerated sea-level rise

Dendritic Cell Responses to Early Murine Cytomegalovirus Infection: Subset Functional Specialization and Differential Regulation by Interferon α/β

Differentiation of dendritic cells (DCs) into particular subsets may act to shape innate and adaptive immune responses, but little is known about how this occurs during infections. Plasmacytoid dendritic cells (PDCs) are major producers of interferon (IFN)-α/β in response to many viruses. Here, the functions of these and other splenic DC subsets are further analyzed after in vivo infection with murine cytomegalovirus (MCMV). Viral challenge induced PDC maturation, their production of high levels of innate cytokines, and their ability to activate natural killer (NK) cells. The conditions also licensed PDCs to efficiently activate CD8 T cells in vitro. Non-plasmacytoid DCs induced T lymphocyte activation in vitro. As MCMV preferentially infected CD8α+ DCs, however, restricted access to antigens may limit plasmacytoid and CD11b+ DC contribution to CD8 T cell activation. IFN-α/β regulated multiple DC responses, limiting viral replication in all DC and IL-12 production especially in the CD11b+ subset but promoting PDC accumulation and CD8α+ DC maturation. Thus, during defense against a viral infection, PDCs appear specialized for initiation of innate, and as a result of their production of IFN-α/β, regulate other DCs for induction of adaptive immunity. Therefore, they may orchestrate the DC subsets to shape endogenous immune responses to viruses

Late Glacial to Holocene relative sea-level change in Assynt, northwest Scotland, UK

Relative sea-level change (RSL), from the Late Glacial through to the late Holocene, is reconstructed for the Assynt region, northwest Scotland, based on bio- and lithostratigraphical analysis. Four new radiocarbon-dated sea-level index points help constrain RSL change for the Late Glacial to the late Holocene. These new data, in addition to published material, capture the RSL fall during the Late Glacial and the rise and fall associated with the mid-Holocene highstand. Two of these index points constrain the Late Glacial RSL history in Assynt for the first time, reconstructing RSL falling from 2.47 ± 0.59 m OD to 0.15 ± 0.59 m OD at c. 14,000–15,000 cal yr BP. These new data test model predictions of glacial isostatic adjustment (GIA), particularly during the early deglacial period which is currently poorly constrained throughout the British Isles. Whilst the empirical data from the mid- to late-Holocene to present matches quite well with the recent GIA model output, there is a relatively poor fit between the timing of the Late Glacial RSL fall and early Holocene RSL rise. This mismatch, also evident elsewhere in northwest Scotland, may result from uncertainties associated with both the global and local ice components of GIA models.</jats:p

Granulocyte Macrophage Colony-Stimulating Factor: A New Putative Therapeutic Target in Multiple Sclerosis

Experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, can be induced by immunization with a number of myelin antigens. In particular, myelin oligodendrocyte glycoprotein, a central nervous system (CNS)-specific antigen expressed on the myelin surface, is able to induce a paralytic MS-like disease with extensive CNS inflammation and demyelination in several strains of animals. Although not well understood, the egress of immune cells into the CNS in EAE is governed by a complex interplay between pro and antiinflammatory cytokines and chemokines. The hematopoietic growth factor, granulocyte macrophage colony-stimulating factor (GM-CSF), is considered to play a central role in maintaining chronic inflammation. The present study was designed to investigate the previously unexplored role of GM-CSF in autoimmune-mediated demyelination. GM-CSF−/− mice are resistant to EAE, display decreased antigen-specific proliferation of splenocytes, and fail to sustain immune cell infiltrates in the CNS, thus revealing key activities for GM-CSF in the development of inflammatory demyelinating lesions and control of migration and/or proliferation of leukocytes within the CNS. These results hold implications for the pathogenesis of inflammatory and demyelinating diseases and may provide the basis for more effective therapies for inflammatory diseases, and more specifically for multiple sclerosis

Urokinase-type plasminogen activator and arthritis progression: role in systemic disease with immune complex involvement

INTRODUCTION: Urokinase-type plasminogen activator (u-PA) has been implicated in fibrinolysis, cell migration, latent cytokine activation, cell activation, T-cell activation, and tissue remodeling, all of which are involved in the development of rheumatoid arthritis. Previously, u-PA has been reported to play a protective role in monoarticular arthritis models involving mBSA as the antigen, but a deleterious role in the systemic polyarticular collagen-induced arthritis (CIA) model. The aim of the current study is to determine how u-PA might be acting in systemic arthritis models. METHODS: The CIA model and bone marrow chimeras were used to determine the cellular source of u-PA required for the arthritis development. Gene expression of inflammatory and destructive mediators was measured in joint tissue by quantitiative PCR and protein levels by ELISA. The requirement for u-PA in the type II collagen mAb-induced arthritis (CAIA) and K/BxN serum transfer arthritis models was determined using u-PA(-/-) mice. Neutrophilia was induced in the peritoneal cavity using either ovalbumin/anti-ovalbumin or the complement component C5a. RESULTS: u-PA from a bone marrow-derived cell was required for the full development of CIA. The disease in u-PA(-/-) mice reconstituted with bone marrow from C57BL/6 mice was indistinguishable from that in C57BL/6 mice, in terms of clinical score, histologic features, and protein and gene expression of key mediators. u-PA(-/-) mice were resistant to both CAIA and K/BxN serum transfer arthritis development. u-PA(-/-) mice developed a reduced neutrophilia and chemokine production in the peritoneal cavity following ovalbumin/anti-ovalbumin injection; in contrast, the peritoneal neutrophilia in response to C5a was u-PA independent. CONCLUSIONS: u-PA is required for the full development of systemic arthritis models involving immune complex formation and deposition. The cellular source of u-PA required for CIA is bone marrow derived and likely to be of myeloid origin. For immune complex-mediated peritonitis, and perhaps some other inflammatory responses, it is suggested that the u-PA involvement may be upstream of C5a signaling

A Comparison of Cooling Techniques to Treat Cardiac Arrest Patients with Hypothermia

Introduction. We sought to compare the performance of endovascular cooling to conventional surface cooling after cardiac arrest. Methods. Patients in coma following cardiopulmonary resuscitation were cooled with an endovascular cooling catheter or with ice bags and cold-water-circulating cooling blankets to a target temperature of 32.0–34.0°C for 24 hours. Performance of cooling techniques was compared by (1) number of hourly recordings in target temperature range, (2) time elapsed from the written order to initiate cooling and target temperature, and (3) adverse events during the first week. Results. Median time in target temperature range was 19 hours (interquartile range (IQR), 16–20) in the endovascular group versus. 10 hours (IQR, 7–15) in the surface group (P = .001). Median time to target temperature was 4 (IQR, 2.8–6.2) and 4.5 (IQR, 3–6.5) hours, respectively (P = .67). Adverse events were similar. Conclusion. Endovascular cooling maintains target temperatures better than conventional surface cooling

The prevalence and correlates of texting while driving among a population-based sample of Ontario students

Objective: Texting while driving (TWD) has a deleterious impact on driving performance and may pose a significant challenge to traffic safety. This challenge may be particularly relevant for young and inexperienced drivers. This study examined the prevalence and risk factors of writing text messages or emails while driving during the past 12 months. Method: This study analyzed a subpopulation of 1,133 licensed students 16 years of age or older from the 2013 Ontario Student Drug Use Survey (OSDUHS), a population-based survey of students in Ontario, Canada. Results: Our results indicate that 36% of licensed drivers reported writing a text message while driving during the past 12 months; of those who did, 56% reported doing so 4 or more times. Graduated licensing was the strongest factor predicting TWD. Compared to students with the more restrictive G1 license, students with a G2 or full license were 9.4 times more likely to report TWD after controlling for the effect of all other factors. Older students, white students, and students attending school in urban centers were more likely to report TWD, and the amount of time spent on social media sites, being a passenger with a driver using substances, and past-year collisions were also significantly associated with TWD. Gender differences and participation in driver education training were not associated with TWD. Conclusions: This research demonstrates that TWD is an extremely common behavior among licensed student drivers in Ontario, particularly among those who have passed the first stage of graduated licensing. TWD is associated with other risky driving behaviors and outcomes, and the findings from this study underscore the need to better understand the harms associated with this behavior

Identifying cortical structure markers of resilience to adversity in young people using surface-based morphometry

Previous research on the neurobiological bases of resilience in youth has largely used categorical definitions of resilience and voxel-based morphometry methods that assess gray matter volume. However, it is important to consider brain structure more broadly as different cortical properties have distinct developmental trajectories. To address these limitations, we used surface-based morphometry and data-driven, continuous resilience scores to examine associations between resilience and cortical structure. Structural MRI data from 286 youths (Mage = 13.6 years, 51% female) who took part in the European multi-site FemNAT-CD study were pre-processed and analyzed using surface-based morphometry. Continuous resilience scores were derived for each participant based on adversity exposure and levels of psychopathology using the residual regression method. Vertex-wise analyses assessed for correlations between resilience scores and cortical thickness, surface area, gyrification and volume. Resilience scores were positively associated with right lateral occipital surface area and right superior frontal gyrification and negatively correlated with left inferior temporal surface area. Moreover, sex-by-resilience interactions were observed for gyrification in frontal and temporal regions. Our findings extend previous research by revealing that resilience is related to surface area and gyrification in frontal, occipital and temporal regions that are implicated in emotion regulation and face or object recognition