63,229 research outputs found

    In Vivo Fluorescence Imaging of E-Selectin: Quantitative Detection of Endothelial Activation in Arthritis

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    Rheumatoid arthritis (RA) is a chronic progressive systemic inflammatory disease, characterized by synovial inflammation and localized destruction of cartilage and bone. Heterogeneity in the clinical presentation of RA and uncertainty about which patients will respond to treatment makes diagnosis and management challenging. Fluorescent imaging in the near infrared (NIR) spectrum significantly decreases tissue autofluorescence offering unique potential to detect specific molecular targets in vivo. E-selectin or endothelial adhesion molecule-1 (ELAM-1), a 115kDa glycoprotein induced on endothelial cells in response to pro-inflammatory cytokines involved in RA, such as interleukin (IL)-1 beta and tumour necrosis factor alpha (TNF alpha). E-selectin has been well validated as a potential biomarker of disease activity. My study aimed to investigate whether E-selectin targeted optical imaging in vivo could be developed as a sensitive, specific and quantifiable preclinical molecular imaging technique, and also whether this approach could be used to delineate the molecular effects of novel therapies. I utilised anti-E-selectin antibody labelled with NIR fluorophore in a mouse model of paw swelling induced by intra-plantar injection of TNF alpha, and in acute collagen-induced arthritis (CIA) in DBA/1 mice, a widely used model of RA. E-selectin generated signal, localised to points of maximal clinical inflammation in the inflamed mouse paw in both models with significant differences to control antibody. Binding of anti-E-selectin antibody was also demonstrated by immunohistochemistry in both models. The ability of E-selectin targeted imaging to detect sub-clinical endothelial activation was also investigated, demonstrating that E-selectin may be an excellent way of determining subclinical vascular activation in CIA. Finally the effect of novel targeted therapy – RB200 which blocks epidermal growth factor (EGF) signalling was investigated. This demonstrated that E-selectin targeted signal could be absolutely abrogated to a level seen in unimmunised healthy control animals, following combination treatment with RB200 and the TNF alpha inhibitor etanercept. E-selectin targeted optical imaging is a viable in vivo imaging technique that can also be applied to quantify disease and investigate the effects of novel molecular therapies. It holds significant promise as a molecular imaging technique for future translation into the clinic for patients with rheumatoid arthritis and other inflammatory diseases

    Optimal Use of Rewards as Commitment Device When Bidding is Costly

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    This paper considers procurement auctions with costly bidding when the auctioneer is unable to commit himself to restrict the number of bidders. The auctioneer can, however, offer a financial reward to be paid to every short-listed bidders as an indirect commitment device. Rewards for short-listed bidders are costly. Nevertheless, it is generally optimal for the procurer to credibly implement the same restriction of the number of bidders that is optimal under full commitment

    The Sussex occupation and the privatisation of university education

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    The outsourcing of campus services is part of a wider process where UK universities are becoming more like businesses. Private companies are moving into the sector, facilitated by government. This is to the detriment of employees, campus community and collective dialogue. Privatisation is spreading to academia, and learning is becoming less about social benefit and the value of education, and more about what’s commercially profitable. This will change the shape and content of the curriculum

    The Forgotten Right "to Be Secure"

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    Surveillance methods in the United States operate under the general principle that “use precedes regulation.” While the general principle of “use precedes regulation” is widely understood, its societal costs have yet to be fully realized. In the period between “initial use” and “regulation,” government actors can utilize harmful investigative techniques with relative impunity. Assuming a given technique is ultimately subjected to regulation, its preregulation uses are practically exempted from any such regulation due to qualified immunity (for the actor and municipality) and the exclusionary rule’s good faith exception (for any resulting evidence). This expectation of impunity invites strategic government actors to make frequent and arbitrary uses of harmful investigative techniques during preregulation periods. Regulatory delays tend to run long (often a decade or more) and are attributable in no small part to the stalling methods of law enforcement (through assertions of privilege, deceptive funding requests, and strategic sequencing of criminal investigations). While the societal costs of regulatory delay are high, rising, and difficult to control, the conventional efforts to shorten regulatory delays (through expedited legislation and broader rules of Article III standing) have proved ineffective. This Article introduces an alternative method to control the costs of regulatory delay: locating rights to be “protected” and “free from fear” in the “to be secure” text of the Fourth Amendment. Courts and most commentators interpret the Fourth Amendment to safeguard a mere right to be “spared” unreasonable searches and seizures. A study of the “to be secure” text, however, suggests that the Amendment can be read more broadly: to guarantee a right to be “protected” against unreasonable searches and seizures, and possibly a right to be “free from fear” against such government action. Support for these broad readings of “to be secure” is found in the original meaning of “secure,” the Amendment’s structure, and founding-era discourse regarding searches and seizures. The rights to be “protected” and “free from fear” can be adequately safeguarded by a judicially-created rule against government “adoption” of an investigative method that constitutes an unregulated and unreasonable search or seizure. The upshot of this Fourth Amendment rule against “adoption” is earlier standing to challenge the constitutionality of concealed investigative techniques. Earlier access to courts invites earlier j

    Student Pieces: My Generation: headed in two directions

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