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Post-stroke cognitive impairment and dementia (PSCID) affects many survivors of large vessel cerebral ischemia. The molecular pathways underlying PSCID are poorly defined but may overlap with neurodegenerative pathophysiology. Specifically, synaptic dysfunction after stroke may be directly mediated by alterations in the levels of amyloid beta (Aβ), the peptide that accumulates in the brains of Alzheimer’s disease (AD) patients. In this study, we use the transient middle cerebral artery occlusion (MCAo) model in young adult mice to evaluate if a large vessel stroke increases brain soluble Aβ levels. We show that soluble Aβ40 and Aβ42 levels are increased in the ipsilateral hippocampus in MCAo mice 7 days after the injury. We also analyze the level and activity of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), an enzyme that generates Aβ in the brain, and observe that BACE1 activity is increased in the ipsilateral hippocampus of the MCAo mice. Finally, we highlight that treatment of MCAo mice with a BACE1 inhibitor during the recovery period rescues stroke-induced deficits in hippocampal synaptic plasticity. These findings support a molecular pathway linking ischemia to alterations in BACE1-mediated production of Aβ, and encourage future studies that evaluate whether targeting BACE1 activity improves the cognitive deficits seen with PSCID.

Evaluative performances, such as conservatory examinations and competitions, frequently play a significant role in piano instruction in many parts of the world. Many students participate in these performances as a result of the perception that a program of instruction that is focused on standardized curriculum and evaluation practices will be of higher quality and will result in higher levels of student motivation. This study employs grounded theory methodology and narrative inquiry to better understand the experiences of beginning and intermediate piano students. The findings consist of characteristics of positive experiences with evaluative performances as well as factors that contribute to the quality of students’ experiences. Students who had positive experiences with evaluative performances reported positive emotional responses, perceptions of meaningful music learning, and strengthened musical identity. In order for students to have positive experiences with evaluative performances, their understandings, values, goals, and characteristics as a performer needed to align with the demands of the evaluation. In addition, positive experiences with evaluative performances required the presence of supportive relationships with parents and teachers. This article concludes with pedagogical implications.

Objective The objective of this paper is to investigate the safety, pharmacokinetics (PK) and immunogenicity of CDP7657, a PEGylated anti-CD40L antibody fragment, in healthy individuals and patients with systemic lupus erythematosus (SLE). Methods This randomized, double-blind, single-dose, dose-escalation phase I study consisted of two parts. In part 1, 28 healthy individuals received CDP7657 IV (0.004–5 mg/kg) or placebo. In part 2, 17 patients with SLE received CDP7657 IV (5–60 mg/kg) or placebo. The CDP7657:placebo ratio was 3:1. Results Adverse events (AEs) were reported by 76% of healthy individuals and 100% of patients with SLE treated with CDP7657; most were mild or moderate in intensity. Two healthy individuals reported serious AEs (SAEs), one of which was considered treatment related (infusion-related reaction; 5 mg/kg cohort). One patient with SLE (60 mg/kg cohort) experienced three SAEs, one of which was considered treatment related (herpes zoster infection). No thromboembolic events were reported. CPD7657 exposure increased in a dose-proportional manner. Low anti-CDP7657 antibody titres were detected in the majority of CDP7657-treated participants with no apparent impact on the PK of CDP7657. Conclusion Single doses of CDP7657 showed predictable PK in healthy individuals and patients with SLE and were well tolerated, with no safety signals of concern. These findings support further investigation of CDP7657 as a therapy for SLE.

Cardiovascular interventions—in the form of bypass grafts, stents, prosthetic valves, and ventricular assist devices—are increasingly common for the typical citizen of the industrialized world. While these certainly contribute to longevity and improved quality of life, they can also be a source of morbidity and mortality. In most cases, a handful of predictable pathogenic pathways underlie the eventual degeneration or failure of the various interventions, and may be implicated as a cause of death. Much less frequently, an untoward and unexpected complication can be the culprit. The objectives of this manuscript are to describe the more common cardiac interventions (both mechanical and surgical), highlight the typical failure modes, and present approaches to evaluate devices and grafts when encountered in the forensic autopsy suite.

National Heritage Areas (NHAs) are an alternative and increasingly popular form of protected area management in the United States. NHAs seek to integrate environmental objectives with community and economic objectives at regional or landscape scales. NHA designations have increased rapidly in the last 20 years, generating a substantial need for evaluative information about (a) how NHAs work; (b) outcomes associated with the NHA process; and (c) the costs and benefits of investing public moneys into the NHA approach. Qualitative evaluation studies recently conducted at three NHAs have identified the importance of understanding network structure and function in the context of evaluating NHA management effectiveness. This article extends these case studies by examining quantitative network data from each of the sites. The authors analyze these data using both a descriptive approach and a statistically more robust approach known as exponential random graph modeling. Study findings indicate the presence of transitive structures and the absence of three-cycle structures in each of these networks. This suggests that these networks are relatively ‘‘open,’’ which may be desirable, given the uncertainty of the environments in which they operate. These findings also suggest, at least at the sites reported here, that the NHA approach may be an effective way to activate and develop networks of intersectoral organizational partners. Finally, this study demonstrates the utility of using quantitative network analysis to better understand the effectiveness of protected area management models that rely on partnership networks to achieve their intended outcomes.

To protect children with allergies, schools are being pressured to become peanut-free zones. Medical and legal experts say that's not a good idea.

IMAGINE the exhilaration as high school students throughout the country suit up for their first practice, polish their instruments, and prepare for their upcoming games and events with high-fives all around. This excitement, however, is quickly replaced with anxiety, even dismay, as many of these same students learn that they must first pay a participation fee, which may mean they will not be able to take part after all. "Pay-to-play" is catching on across the country--sometimes with harsh consequences for students and schools. No one doubts that the cost of running a school district is staggering. Fuel for heat and buses, salaries and benefits for employees, and ever-changing curricular demands combine to put enormous pressure on superintendents and school boards to cut spending and raise revenues. In many districts, state and local funding is shrinking, and extracurricular activities are often the first items to be put on the chopping block. (1) Extracurricular activities, particularly sports, have a longstanding tradition in public schools. School teams were originally seen as a means of giving boys a way to channel their energy in a positive direction while giving the entire student body a rallying point for school pride. Over the years, both the scope and inclusiveness of such programs have expanded, and the benefits of sports and other activities have been well-documented by practitioners and scholars alike. (2) Meanwhile, the cost of running extracurricular programs has risen steeply. The cost for transporting students to competitions or conferences has increased for all competitive clubs and activities, as have the stipends for club sponsors. Expenditures for sports, however, have increased the most dramatically. As competition and the potential for college scholarships have increased, so have the costs of maintaining competitive programs, which demand expert coaching, high-tech training equipment, and better facilities. In addition, the litigious nature of our society pressures schools into buying the best protective equipment for athletes, adding coaches for increased supervision, and paying for additional liability insurance. It is no wonder that many schools are looking for ways to offset the heavy costs of these extracurricular programs. Enter the concept of pay-to-play, which shifts some of the financial burden of extracurricular activities to students and their families. At the low end of the price spectrum, some school districts in Maine recently enacted policies to charge fees ranging from $15 to $50 a year for any student who wishes to participate in any number of extracurricular activities. At the high end, a high school on the West Coast charges students for each sport or activity, with fees of $1,500 for cheerleading, $1,000 for football, and $800 for marching band. (3) And in the states in between, fees range widely but are clearly becoming more and more common. A poll taken in 2004 showed that 34 states had at least some schools charging fees for extracurricular participation. (4) Whether the fee is large or small, however, is beside the point. Once established, fees tend to increase as the costs of programs escalate and as parents become desensitized to the policy. More crucial are what these fees represent for our "public" school system and the potentially negative consequences for students--particularly those from underprivileged families, for whom fees can represent significant barriers to participation. Some schools make the argument that they have "fee waivers" for those who cannot afford to pay. While such concessions are well meant, we believe that pay-to-play remains a bad idea. Whether priced high or low, with or without fee waivers, the policy is indefensible from a legal perspective, from a student's perspective, and from a societal perspective. The negative consequences are not offset by the limited revenues generated. LEGAL CONSIDERATIONS State constitutions across the nation include guarantees of "free public education. …

Tissue microarray (TMA) technology allows the miniaturization and characterization of multiple tissue samples on a single slide and commonly uses formalin-fixed paraffin-embedded (FFPE) tissue or acetone-fixed frozen tissue. The former provides good morphology but can compromise antigenicity, whereas the latter provides compromised morphology with good antigenicity. Here, we report the development of TMAs in glycol methacrylate resin, which combine the advantages of both methods in one embedding format. Freshly collected tissue fixed in -20C acetone or 10% neutral buffered formaldehyde were cored and arrayed into an intermediary medium of 2% agarose before infiltration of the agarose array with glycol methacrylate resin. Acetone-fixed resin TMA demonstrated improved morphology over acetone-fixed frozen TMA, with no loss of antigenicity. Staining for extracellular, cell surface, and nuclear antigens could be realized with monoclonal and polyclonal antibodies as well as with monomeric single-chain Fv preparations. In addition, when compared with FFPE TMA, formalin-fixed tissue in a resin TMA gave enhanced morphology and subcellular detail. Therefore, resin provides a universal format for the construction of TMAs, providing improved tissue morphology while retaining antigenicity, allows thin-section preparation, and could be used to replace preparation of frozen and FFPE TMAs for freshly collected tissue.

This paper considers the role of covariates when using predicted probabilities to interpret main effects and interactions in logit models. While predicted probabilities are very intuitive for interpreting main effects and interactions, the pattern of results depends on the contribution of covariates. We introduce a concept called the covariate contribution, which reflects the aggregate contribution of all of the remaining predictors (covariates) in the model and a family of tools to help visualize the relationship between predictors and the predicted probabilities across a variety of covariate contributions. We believe this strategy and the accompanying tools can help researchers who wish to use predicted probabilities as an interpretive framework for logit models acquire and present a more comprehensive interpretation of their results. These visualization tools could be extended to other models (such as binary probit, multinomial logistic, ordinal logistic models, and other nonlinear models).

When analyzing data from a randomized experiment that is replicated across multiple sites and includes covariates, the covariates can adjust for differences from either the grand mean or the group (site) mean. The analysis strategy determines the reference point. Pooling the sites and using a standard analysis of covariance (ANCOVA) adjusts for differences around the grand mean, whereas analyzing each site separately adjusts for differences around each group (site) mean. This article demonstrates that group mean centering permits pooling data from multiple sites into a single analysis while still using the group mean as a reference point for evaluating the covariate.

Microinjection of a serotonergic 5-HT1Bagonist (S-CM-GTNH2, 3μg/l) into the dorsal subiculum (DS) induced long-lasting increases in dopamine (DA; +58%), dihydroxyphenylacetic acid (DOPAC; +15%) and homovanillic acid (HVA; +31%), without changing extracellular levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), measured by microdialysis in freely moving rats in the shell area of the nucleus accumbens (n. acc). Perfusion of a glutamate-N-methyl-D-aspartate (NMDA) receptor antagonist (MK 801, dizocilpine, 10μM) through the dialysis probe in the n. acc induced similar long-lasting increases in DA and DOPAC, whereas the glutamate-quisqualate/kainate receptor antagonist (CNQX, 50 μM) had no effect. In the presence of dizocilpine in the n. acc, microinjection of S-CM-GTNH2into the DS could still increase DOPAC and HVA, but DA levels were not further changed, whereas in the presence of CNQX, microinjection of S-CM-GTNH2into the DS still increased not only DOPAC and HVA, but also DA levels in a way similar to that in the absence of glutamate antagonist. Therefore, activation of 5-HT1Breceptors located in the DS increases the release of DA in the n. acc, presumably via the glutamatergic projection to this structure and acting through NMDA receptors in it. This implies either the suppression of a tonic indirect inhibitory influence and/or stimulation of a phasic excitatory effect of glutamate.Disruption of latent inhibition (LI) has been suggested as a model for a cognitive deficit in schizophrenia (hyperattention to irrelevant stimuli) and is usually associated with an increase in DA release in the n. acc. However, s.c. injection of RU 24 969 (0.5 mg/kg), a mixed 5-HT1A-5-HT1Bagonist, which was previously shown to increase DA release in the n. acc, left LI unchanged. Moreover, bilateral microinjections of S-CM-GTNH2into the rat DS tended to potentiate LI, in spite of the increase in DA in n. acc demonstrated here. It is concluded that not all increases in DA release in the n. acc are functionally equivalent. Sensitization of receptors or impulse- dependent increase in DA release might be necessary to disrupt LI. The possible role of altered serotonergic transmission, through h5-HT1Breceptors (human homologue of the rat 5-HT1Breceptors) located in the DS, in acute schizophrenia needs to be further investigated.

Allograft coronary artery disease (CAD) remains the leading cause of morbidity and mortality affecting the long-term survival of patients after cardiac transplantation. Because there is increasing evidence that imbalances in hemostatic and fibrinolytic pathways are associated with graft failure, we hypothesized that atherothrombotic risk factors may contribute to allograft CAD. This study sought to determine if plasma hemostatic and fibrinolytic parameters are associated with the severity of allograft CAO. The extent of allograft CAD was investigated by angiography and intravascular ultrasound (IVUS) in 16 cardiac transplant recipients. Intimal thickening was quantified using IVUS by measuring the intimal index (li = intimal area/[intimal area + luminal area]) in two to five segments of the left anterior descending (LAD) coronary artery. The maximal li per patient was calculated and index to the time post-transplant (Mxli/Yr). Plasma fibrinogen (FGN), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), lipoprotein(a) (Lp(a)), and net fibrinolytic activity of plasma were assayed 6−24 months after transplant as indicators of the fibrinolytic system and then correlated with the IVUS measurements. The FGN level correlated with the severity of initimal thickening, Mxli/Yr ( r2 = 0.41, p = 0.008), and was inversely correlated with angiographic tertiary vessel filling ( r2 = −0.25, p = 0.051). In patients with lower plasma fibrinolytic activity (lytic zone less than 100 mm2), Mxli/Yr was increased eightfold (0.218 ± 0.137 versus 0.025 ± 0.021, p = 0.001). t-PA ( r2 = 0.0004, p = 0.94), PAI-1 ( r2 = 0.008, p = 0.75) and Lp(a) levels ( r2 = 0.11, p = 0.21) did not predict Mxli/Yr. Thus, we demonstrate that plasma FGN and net fibrinolytic activity correlate with the degree of intimal thickening measured by IVUS after cardiac transplantation. These data suggest that fibrin deposition may play a role in allograft CAD after cardiac transplantation.

Tax controls are one of the leading alternatives to drug prohibition. The impact, success and acceptability of drug taxes depends, however, on which tax model is applied. This article examines political, economic and legal drug tax models and concludes that a retributive model, which is similar to an efficiency-based tax, is the best choice. The article examines revenue potential and considers how drug tax monies should be spent. Criticisms of tax controls are also considered.

CONTESTS between nations take various forms depending upon their resources and financial ability, their possessions, means of transportation and communication, their diplomatic aptitude, and their actual armed forces. Armed forces themselves may be regarded as a symptom of a nation's punitive psychology. By their size, organization and distribution, an estimate may be made as to how and in what manner the policies of the states are to be enforced. Within the last generation great changes have come about in the internal organizations of states and in their relations with each other. This condition has been brought about very largely by electrical means of communication which transmit news instantaneously all over the world, thereby distributing thoughts and ideas to a constantly increasingly literate people. Contributing factors have been the added rapidity of transportation both on land and water, the railroad and the steamship. Within the last decade, the advent of air transportation, which is not limited by either seas or continents, has added a totally new element in the relations of nations to each other. So far the domain of air power has been principally a military one, but soon its economic aspects will be even greater. Physical means are employed by nations to impress their will on an adversary only when their other means of adjusting disputes have failed. No nation today will willingly give up a reasonable organization for the defense of its territory, the maintenance of its institutions and the furtherance of its civilization either by civil means, comme cial means, or military means. On the other hand, the nations are perfectly willing to dispense or do away with antiquated means of national defe se which have become obsolete and useless, and which at the same time greatly oppress the people by i creased taxation and services in the building up of industries and classes which cannot be used for anything except war. Leaving out of consideration civil and commercial means of carrying on competitions between nations and viewing the military side alone, we must make an up-to-date appraisal of what military forces consist of and what they are worth in order to arrive at a basis for a limitation of armaments. Armies and navies have heretofore held the stage, but now air power has appeared on the scene. Air power has completely changed the relation of armies to navies and navies to armies, and both of these bear an entirely new relation to air power.