Background-Thinning of the tunica media and rarefaction of smooth muscle cells (SMCs) characterize aneurysmal aortas. Apoptosis determines the cellularity and morphogenesis of tissue. Macrophages and T lymphocytes infiltrate the wall of abdominal aortic aneurysms (AAAs) and produce death-promoting proteins (perforin, Fas, and FasL). This study investigated whether apoptosis occurs in association with the expression of these proteins. Methods and Results-We examined signs of apoptosis and expression of death-promoting mediators in segments of AAAs from patients undergoing elective repair (nϭ20). Anti-␣-actin immunostaining showed a reduced number of SMCs in AAAs. In situ terminal transferase-mediated dUTP nick end-labeling (TUNEL) showed higher levels of DNA fragmentation in AAAs than in controls (nϭ5). The AAA walls contained more cells bearing markers of apoptosis than normal aorta (PϽ0.05, Student's t test). Double immunostaining identified SMCs and macrophages as the principal cell types displaying fragmented DNA. Immunohistochemistry revealed that AAAs but not normal aorta contained CD4

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Whether or not adults receive a prescription for any antibiotic during a 12 month period does not appear to influence the antimicrobial resistance of perineal flora. However, the temporal and dose-response relationships found may be suggestive of a causative association and should be the focus of further research.

Objective measurement of the built environment in inpatient psychiatric settings is feasible and can be used to identify features that increase user satisfaction.

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Methylphenidate treatment is used for Attention Deficit Hyperactivity Disorder and can improve learning and memory. Previously, improvements were considered a by-product of increased attention; however, we hypothesize that methylphenidate directly alters mechanisms underlying learning and memory, and therefore examined its effects on hippocampal long-term potentiation and long-term depression. Methylphenidate enhanced both mechanisms in the absence of presynaptic changes and in a noradrenalin ␤-receptor-dependent manner. These findings can explain both the improved learning and memory and decreased learning selectivity found with methylphenidate treatment and constitute the first demonstration of direct actions of methylphenidate on mechanisms implicated in cognition.Attention Deficit Hyperactivity Disorder (ADHD) affects 8%-12% of children (Biederman and Faraone 2005) and is characterized by inattention, hyperactivity, and impulsivity. Consequences of the disorder include poorer academic performance, employment records, social relationships, and a higher risk of drug abuse (Doggett 2004). While behavioral, cognitive, and psychosocial therapies exist for ADHD, they are often ineffective unless combined with pharmacological treatment , the most common of which is the psychostimulant, methylphenidate (Ritalin, Concerta). Methylphenidate is known to increase extracellular dopamine and noradrenalin Segal 1997, 2002), but not serotonin (Kuczenski and Segal 1997) suggesting that therapeutic efficacy relates to alterations in dopamine and noradrenalin. Despite knowledge of these neurochemical effects, the mechanisms contributing to the effectiveness of methylphenidate are unclear (Safer and Allen 1989; National Institutes of Health Consensus Development Conference Statement 2000;Greenhill 2001).One clue to mechanisms of efficacy can be found at a behavioral level, where methylphenidate improves academic performance (Yang et al. 2004;McGough et al. 2006), working (Wright and White 2003) and visual (Rhodes et al. 2004) memory, nonverbal (O'Toole et al. 1997) and visuospatial (Bedard et al. 2004) learning, and reading skills (Keulers et al. 2007), which may explain why, in addition to its medicinal use, it is used illegally by healthy students to aid study (Teter et al. 2006). Despite evidence of methylphenidate-induced changes in learning and memory, the mechanisms underlying these changes have received little focus and are commonly assumed to be a by-product of improved attention. However, we suggest that these findings are the result of direct actions of methylphenidate on learning and memory mechanisms.In support of this hypothesis, methylphenidate has been shown to increase hippocampal noradrenalin in vivo (Kuczenski and Segal 2002), and such changes are known to impact on plasticity such as long-term potentiation (LTP) and long-term depression (LTD) (Hopkins and Johnston 1984;Izumi et al. 1992;Sah and Bekkers 1996;Thomas et al. 1996;Izumi and Zorumski 1999;Schimanski et al. 2007;Lin et al. 2008), both of which a...

The PD-1/PD-L1 pathway is a key immune checkpoint that regulates T cell activation. There is strong rationale to develop PD-1 agonists as therapeutics against autoimmunity, but progress in this area has been limited. Here, we generated TCR targeting, PD-1 agonist bispecifics called ImmTAAI molecules that mimic the ability of PD-L1 to facilitate the co-localization of PD-1 with the T cell receptor (TCR) complex at the target cell-T cell interface. PD-1 agonist ImmTAAI molecules specifically bound to target cells and were highly effective in activating the PD-1 receptor on interacting T cells to achieve immune suppression. Potent PD-1 antibody ImmTAAI molecules closely mimicked the mechanism of action of endogenously expressed PD-L1 in their localization to the target cell-T cell interface, inhibition of proximal TCR signalling events and suppression of T cell function. At picomolar concentrations, these bispecifics suppressed cytokine production and inhibited CD8 T cell-mediated cytotoxicity in vitro. Crucially, in soluble form the PD-1 ImmTAAI molecules were inactive and hence could avoid systemic immunosuppression. This study outlines a promising new route to generate more effective, potent, tissue-targeted PD-1 agonists that can inhibit T cell function locally with the potential to treat autoimmune and chronic inflammatory diseases of high unmet need.

Mounting evidence indicates issues with low adherence to existing consensus-based guidelines for conducting systematic reviews (SRs), meaning that SRs can be subject to selective or misreporting practices. This problem arises in part from scarce guidance for reproducible reporting practices. This is compounded by the fact that existing guidelines are mainly applicable to interventional research designs, with systematic reviewers of non-interventional studies resorting to customised tools that deviate from best practice. Here, we present the development of the first comprehensive tool for conducting and reporting Non-Interventional, Reproducible, and Open Systematic Reviews (NIRO-SR). NIRO-SR is a 68-item checklist composed of two parts that provide itemised guidance on the preparation of a protocol for pre-registration (Part A) and reporting the review (Part B) in a reproducible and transparent manner. This paper, the tool, and an open repository (https://osf.io/f3brw/) provide a comprehensive resource for anyone who aims to conduct a high quality SR of non-interventional studies.