Cyclooxygenase-2 inhibition prevents delayed death of CA1 hippocampal neurons following global ischemia

The inducible isoform of the enzyme cyclooxygenase-2 (COX2) is an immediate early gene induced by synaptic activity in the brain. COX2 activity is an important mediator of inflammation, but it is not known whether COX2 activity is pathogenic in brain. To study the role of COX2 activity in ischemic injury in brain, expression of COX2 mRNA and protein and the effect of treatment with a COX2 inhibitor on neuronal survival in a rat model of global ischemia were determined. Expression of both COX2 mRNA and protein was increased after ischemia in CA1 hippocampal neurons before their death. There was increased survival of CA1 neurons in rats treated with the COX2-selective inhibitor SC58125 [1-[(4-methylsulfonyl) phenyl]-3-trifluoro-methyl-5-[(4-fluoro)phenyl] pyrazole] before or after global ischemia compared with vehicle controls. Furthermore, hippocampal prostaglandin E2 concentrations 24 h after global ischemia were decreased in drug-treated animals compared with vehicle-treated controls. These results suggest that COX2 activity contributes to CA1 neuronal death after global ischemia.     

Expression of the apoptosis-effector gene, Bax, is up-regulated in vulnerable hippocampal CA1 neurons following global ischemia

The observation that delayed death of CA1 neurons after global ischemia is inhibited by protein synthesis inhibitors suggests that the delayed death of these neurons is an active process that requires new gene expression. Delayed death in CA1 has some of the characteristics of apoptotic death; however, candidate proapoptotic proteins have not been identified in the CA1 after ischemia. We studied the expression of Bax protein and mRNA, a member of the bcl-2 family that is an effector of apoptotic cell death, after global ischemia in the four-vessel global ischemia model in the rat and compared these results with the expression of the antiapoptotic gene bcl-2. Bax mRNA and protein are both expressed in CA1 before delayed death, whereas bcl-2 protein is not expressed. Bcl-2 protein expression, but not that of Bax, is increased in CA3, a region that is ischemic but less susceptible to ischemic injury. In the dentate gyrus, both Bax and bcl-2 proteins are expressed. The selective expression of Bax in Ca1 supports the hypothesis that Bax could contribute to delayed neuronal death in these vulnerable neurons by an independent mechanism or by forming heterodimers with gene family members other than bcl-2.     

Differentiating the impact of episodic and chronic stressors on hypothalamic-pituitary-adrenocortical axis regulation in young women.

Objective: The goal of this study was to examine the impact of episodic stress and chronic interpersonal stress on indices of HPA regulation. To explore the potential downstream consequences of altered HPA dynamics, the authors also assessed indicators of metabolic control and systemic inflammation. Design: One hundred four medically healthy women between the ages of 15 and 19 participated. Following an in-depth interview of life stress, a sample of blood was drawn through antecubital venipuncture. Over the course of the next 2 days, participants gathered salivary cortisol samples. Main Outcome Measures: Cortisol morning response, cortisol daily output, glucocorticoid receptor (GR) mRNA, C-reactive protein (CRP), insulin, and glucose. Results: The simple presence of episodic stress or chronic interpersonal stress was not reliably associated with cortisol output, GR mRNA, insulin, or glucose. When women were exposed to an episodic stressor in the midst of chronic stress they showed increased cortisol output and reduced expression of GR mRNA. By contrast, when women had low levels of chronic stress, episodic events were associated with decreased cortisol output and increased GR mRNA. Episodic and chronic stress also interacted to predict CRP, but not insulin or glucose. Conclusions: The impact of episodic stress is accentuated in the midst of chronic interpersonal stress and diminished in its absence. Simultaneous exposure to episodic and chronic stress may create wear and tear on the body, whereas exposure to episodic stress in the context of a supportive environment may toughen the body, protecting it against subsequent stressors. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Utilization-focused evaluation of acute care nurse practitioner role

Using nurse practitioners in acute care is a relatively new phenomenon with little existing data on related expectations and effectiveness. This article describes one organization's program evaluation of the Advanced Practice Registered Nurse (APRN) role. It includes a conceptual model as well as pragmatic data on: perception of the performance of agreed-upon role expectations, influence on targeted aspects of care, retention of a focus on nursing, and factors facilitating or hindering APRN effectiveness.     

Induction of caspase-3-like protease may mediate delayed neuronal death in the hippocampus after transient cerebral ischemia

Delayed neuronal death after transient cerebral ischemia may be mediated, in part, by the induction of apoptosis-regulatory gene products. Caspase-3 is a newly characterized mammalian cysteine protease that promotes cell death during brain development, in neuronal cultures, and in other cell types under many different conditions. To determine whether caspase-3 serves to regulate neuronal death after cerebral ischemia, we have (1) cloned a cDNA encoding the rat brain caspase-3; (2) examined caspase-3 mRNA and protein expression in the brain using in situ hybridization, Northern and Western blot analyses, and double-labeled immunohistochemistry; (3) determined caspase-3-like activity in brain cell extracts; and (4) studied the effect of caspase-3 inhibition on cell survival and DNA fragmentation in the hippocampus in a rat model of transient global ischemia. At 8-72 hr after ischemia, caspase-3 mRNA and protein were induced in the hippocampus and caudate-putamen (CPu), accompanied by increased caspase-3-like protease activity. In the hippocampus, caspase-3 mRNA and protein were predominantly increased in degenerating CA1 pyramidal neurons. Proteolytic activation of the caspase-3 precursor was detected in hippocampus and CPu but not in cortex at 4-72 hr after ischemia. Double-label experiments detected DNA fragmentation in the majority of CA1 neurons and selective CPu neurons that overexpressed caspase-3. Furthermore, ventricular infusion of Z-DEVD-FMK, a caspase-3 inhibitor, decreased caspase-3 activity in the hippocampus and significantly reduced cell death and DNA fragmentation in the CA1 sector up to 7 d after ischemia. These data strongly suggest that caspase-3 activity contributes to delayed neuronal death after transient ischemia.     

Blunted Cortisol Response to Awakening in Mild to Moderate Depression: Regulatory Influences of Sleep Patterns and Social Contacts.

Cortisol is elevated during severe depression. However, some studies of outpatients suggest reduced cortisol levels, either basal or poststress. More definite evidence of this phenomenon is needed, and correlates that may explain the disparate findings should be identified. Women from the community (37 depressed and 36 nondepressed) completed electronic diaries in order to help researchers assess the cortisol awakening response (CAR), sleep, and social contacts. Depressed women had a blunted CAR compared with nondepressed women. Among the nondepressed but not among depressed women, time of waking, and number of social contacts (especially positive ones) were independently associated with CAR. These psychosocial factors may contribute to a normal CAR, but their regulatory influence may become disrupted during mild to moderate clinical depression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Exploring the Tension between Clarity and Ambiguity in Goal Setting for Innovation

In this article we analyse the role of goal setting for innovation in an R&D context. The literature on goal setting for innovation is inconclusive; some scholars claim that goals should be ambiguous in order to inspire novel ideas, but others claim that clear project goals are important in order to undertake innovation projects in an efficient manner. We aim to explain this inconsistency by taking a more fine‐grained view of innovation where we study goal setting in relation to exploratory aspects such as idea generation separately from exploitatory aspects such as idea implementation. The results from an empirical survey study in the R&D department of an automotive company reveal that a general ambition to be innovative is positively related to all phases of innovation, but the effects of clear project goals are more complex. We found that idea novelty increases under conditions of either high or low levels of goal clarity, whereas mid‐range levels of goal clarity are related to fewer novel ideas. These findings inform existing knowledge about goal setting and innovation, and in particular challenge the body of literature showing that only high levels of ambiguity in goal setting are a fruitful means for innovation.     

Impact of organizational redesign

Little in-depth objective information is available about the outcomes of restructuring or reengineering. One reason for this is the difficulty of conducting traditional research within the context of dynamic organizational development activities. The authors describe an alternative program evaluation approach that proved successful for assessing and enhancing large-scale organizational change in an acute-care medical center. Sample results are presented and recommendations made for increasing an evaluation's usefulness by tailoring reports to the user.