Engaging Stakeholders to Co-design an Academic Practice Strategic Plan in an Integrated Health System: The Key Roles of the Nurse Executive and Planning Team.

As key members of the executive team, nurse executives play an integral role in the planning process and operationalization of strategic imperatives to ensure the overall success of the organization. Nurse executives are leading organizations through transition periods that require transformational leadership. Leaders must design a shared vision and set strategic priorities; empower others to lead; ensure access to resources needed for safe care delivery; and inspire people to meet the demands of the future. Paramount to effective strategic planning and achievement of positive outcomes is a leadership team that engages key stakeholders in the strategic planning process. This article provides an overview of a recently integrated health system's strategic planning process that included the engagement of patients and caregivers. This can serve as a blueprint for others in their efforts to implement a systematic approach for enhancing collaborative academic practice in their organizations.

Isotyping the human TOMM40 variable-length polymorphism by gene amplification and restriction digest.

Recent studies have shown that the translocase of outer mitochondrial membrane 40 homolog (TOMM40) contains a polymorphic poly-T variant, the long variant of which is associated with an increase in AD incidence among APOE 3 carriers. Current methods to isotype the poly-T region rely on long PCR, subcloning and sequencing to distinguish among the allelic variants. While such methods are extremely accurate as well as quantitative in determining the number of T residues in the poly-T region, the process can be cumbersome, time consuming and expensive to employ in routine laboratories. To this end, we have developed a quick and simple method to isotype the human TOMM40 variable length polymorphism using a PCR- and restriction digest-based approach, enabling rapid genotyping of TOMM40 variants.

The role of E2F1 in the development of hypertrophic cardiomyopathy.

The overexpression of the transcription factor, E2F1, induces hypertrophy and apoptosis with cell cycle re-entry in cardiomyocytes in vitro and in vivo, suggesting that targeting E2F1 may have therapeutic potential. Accordingly, we tested the hypothesis that blocking the E2F1-mediated signal transduction pathway prevents cardiac hypertrophy by treating E2F1 knockout mice (E2F1-/-) with either isoproterenol (ISO) or Angiotensin II (ANG). Echocardi-ography was used to measure left ventricular mass index and myocardial performance index, a measure of combined systolic and diastolic left ventricular function. In control mice (E2F1+/+) both ISO and ANG treatments induced cardiac hypertrophy, and impaired ventricular function in ANG treated mice. In contrast to previously published work, E2F1-/- mice also demonstrated a similar pattern of cardiac hypertrophy and function after either treatment. Atrial natriuretic peptide, a molecular marker of hypertrophy and necropsy-determined body weight-normalized left ventricle mass were similarly increased in ISO and ANG treated E2F1+/+ and E2F-/- mice, supporting the echocardiographic data. These data indicate that E2F1 is not necessary for the development of cardiac hypertrophy although studies using an overexpression approach suggest a causal role of E2F1. The reason for this discrepancy is unclear, although it is possible that other E2F-family members (e.g., E2F2) may play a compensatory role. In conclusion, our data demonstrate that cardiac hypertrophy can be induced in an E2F1-independent fashion and suggest that in contrast to previous reports, targeting E2F1 may not be a good therapeutic approach.

Using a nursing balanced scorecard approach to measure and optimize nursing performance.

The authors give an overview of one healthcare organization's experience in developing a nursing strategic plan and nursing balanced scorecard (NBS) using a focused planning process involving strategy mapping. The NBS is being used at this organization to manage the nursing strategic plan by leveraging and improving nursing processes and organizational capabilities as required, based on data and transparent communication of performance results to key stakeholders. Key strategies and insights may help other nurse leaders in developing or refining strategic approaches to measuring nursing performance. Vital to the success of an organization's strategic plan are ongoing endorsement, engagement and visibility of senior leaders. Quality of decisions made depends on the organization's ability to collect data from multiple sources using standardized definitions, mine data and extract them for statistical analysis and effectively present them in a compelling and understandable way to users and decision-makers.

Amyloid-beta42 interacts mainly with insoluble prion protein in the Alzheimer brain.

The prion protein (PrP) is best known for its association with prion diseases. However, a controversial new role for PrP in Alzheimer disease (AD) has recently emerged. In vitro studies and mouse models of AD suggest that PrP may be involved in AD pathogenesis through a highly specific interaction with amyloid-ß (Aß42) oligomers. Immobilized recombinant human PrP (huPrP) also exhibited high affinity and specificity for Aß42 oligomers. Here we report the novel finding that aggregated forms of huPrP and Aß42 are co-purified from AD brain extracts. Moreover, an anti-PrP antibody and an agent that specifically binds to insoluble PrP (iPrP) co-precipitate insoluble Aß from human AD brain. Finally, using peptide membrane arrays of 99 13-mer peptides that span the entire sequence of mature huPrP, two distinct types of Aß binding sites on huPrP are identified in vitro. One specifically binds to Aß42 and the other binds to both Aß42 and Aß40. Notably, Aß42-specific binding sites are localized predominantly in the octapeptide repeat region, whereas sites that bind both Aß40 and Aß42 are mainly in the extreme N-terminal or C-terminal domains of PrP. Our study suggests that iPrP is the major PrP species that interacts with insoluble Aß42 in vivo. Although this work indicated the interaction of Aß42 with huPrP in the AD brain, the pathophysiological relevance of the iPrP/Aß42 interaction remains to be established.

Down-regulation of serum gonadotropins is as effective as estrogen replacement at improving menopause-associated cognitive deficits.

Declining levels of estrogen in women result in increases in gonadotropins such as luteinizing hormone (LH) through loss of feedback inhibition. LH, like estrogen, is modulated by hormone replacement therapy. However, the role of post-menopausal gonadotropin increases on cognition has not been evaluated. Here, we demonstrate that the down-regulation of ovariectomy-driven LH elevations using the gonadotropin releasing hormone super-analogue, leuprolide acetate, improves cognitive function in the Morris water maze and Y-maze tests in the absence of E2. Furthermore, our data suggest that these effects are independent of the modulation of estrogen receptors alpha and beta, or activation of CYP19 and StAR, associated with the production of endogenous E2. Importantly, pathways associated with improved cognition such as CaMKII and GluR1-Ser831 are up-regulated by leuprolide treatment but not by chronic long-term E2 replacement suggesting independent cognition-modulating properties. Our findings suggest that down-regulation of gonadotropins is as effective as E2 in modulating cognition but likely acts through different molecular mechanisms. These findings provide a potential novel protective strategy to treat menopause/age-related cognitive decline and/or prevent the development of AD.

Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure.

While considerable evidence supports the causal relationship between increases in c-Myc (Myc) and cardiomyopathy as a part of a "fetal re-expression" pattern, the functional role of Myc in mechanisms of cardiomyopathy remains unclear. To address this, we developed a bitransgenic mouse that inducibly expresses Myc under the control of the cardiomyocyte-specific MHC promoter. In adult mice the induction of Myc expression in cardiomyocytes in the heart led to the development of severe hypertrophic cardiomyopathy followed by ventricular dysfunction and ultimately death from congestive heart failure. Mechanistically, following Myc activation, cell cycle markers and other indices of DNA replication were significantly increased suggesting that cell cycle-related events might be a primary mechanism of cardiac dysfunction. Furthermore, pathological alterations at the cellular level included alterations in mitochondrial function with dysregulation of mitochondrial biogenesis and defects in electron transport chain complexes I and III. These data are consistent with the known role of Myc in several different pathways including cell cycle activation, mitochondrial proliferation, and apoptosis, and indicate that Myc activation in cardiomyocytes is an important regulator of downstream pathological sequelae. Moreover, our findings indicate that the induction of Myc in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure, and that sustained induction of Myc, leading to cell cycle re-entry in adult cardiomyocytes, represents a maladaptive response for the mature heart.

Down-regulation of aminolevulinate synthase, the rate-limiting enzyme for heme biosynthesis in Alzheimer's disease.

Heme is an essential cell metabolite, intracellular regulatory molecule, and protein prosthetic group. Given the known alterations in heme metabolism and redox metal distribution and the up-regulation of heme oxygenase enzyme in Alzheimer's disease (AD), we hypothesized that heme dyshomeostasis plays a key role in the pathogenesis. To begin testing this hypothesis, we used qRT-PCR to quantify the expression of aminolevulinate synthase (ALAS1) and porphobilinogen deaminase (PBGD), rate-limiting enzymes in the heme biosynthesis pathway. The relative expression of ALAS1 mRNA, the first and rate-limiting enzyme for heme biosynthesis under normal physiological conditions, was significantly (p<0.05) reduced by nearly 90% in AD compared to control. Coordinately, the relative expression of PBGD mRNA, which encodes porphobilinogen deaminase, the third enzyme in the heme synthesis pathway and a secondary rate-limiting enzyme in heme biosynthesis, was also significantly (p<0.02) reduced by nearly 60% in AD brain compared to control and significantly related to apolipoprotein E genotype (p<0.005). In contrast, the relative expression of ALAD mRNA, which encodes aminolevulinate dehydratase, the second and a non-rate-limiting enzyme for heme biosynthesis, was unchanged between the two groups. Taken together, our results suggest regulation of cerebral heme biosynthesis is profoundly altered in AD and may contribute toward disease pathogenesis by affecting cell metabolism as well as iron homeostasis.

The neuronal expression of MYC causes a neurodegenerative phenotype in a novel transgenic mouse.

Many different proteins associated with the cell cycle, including cyclins, cyclin-dependent kinases, and proto-oncogenes such as c-MYC (MYC), are increased in degenerating neurons. Consequently, an ectopic activation of the cell cycle machinery in neurons has emerged as a potential pathogenic mechanism of neuronal dysfunction and death in many neurodegenerative diseases, including Alzheimer's disease. However, the exact role of cell cycle re-entry during disease pathogenesis is unclear, primarily because of the lack of relevant research models to study the effects of cell cycle re-entry on mature neurons in vivo. To address this issue, we developed a new transgenic mouse model in which forebrain neurons (CaMKII-MYC) can be induced to enter the cell cycle using the physiologically relevant proto-oncogene MYC to drive cell cycle re-entry. We show that such cell cycle re-entry results in neuronal cell death, gliosis, and cognitive deficits. These findings provide compelling evidence that dysregulation of cell cycle re-entry results in neurodegeneration in vivo. Our current findings, coupled with those of previous reports, strengthen the hypothesis that neurodegeneration in Alzheimer's disease, similar to cellular proliferation in cancer, is a disease that results from inappropriate cell cycle control.

Evidence for the novel expression of human kallikrein-related peptidase 3, prostate-specific antigen, in the brain.

Human kallikrein-related peptidase 3 (hK3), also known as prostate-specific antigen (PSA), is a 33 kDa single chain glycoprotein belonging to the kallikrein family of serine proteases. With chymotrypsin-like enzymatic activity, hK3 is directly and indirectly involved in a number of diverse biological functions including male fertility, the regulation of cell proliferation, and the inhibition of angiogenesis. The gene encoding hK3, hKLK3, is located on chromosome 19 and its expression has been shown to be regulated by steroid hormones through androgen receptor-mediated transcription. hK3 was once thought to be exclusively expressed and secreted by prostatic epithelial cells, hence the initial name of prostate-specific antigen, but has since been isolated in several nonprostatic tissues and ongoing characterization of alternative splicing variants has found at least 13 distinct mRNA transcripts. The detection of hK3 in cerebrospinal fluid prompted the hypothesis that hK3 may be produced in the brain. To test this notion, in this study we used RT-PCR amplification of brain tissue total RNA and examined hK3 protein by immunohistochemical, and immunoblot analysis. RT-PCR revealed several hK3 mRNA transcripts in the brain. Confirming these findings, both immunohistochemical staining and western immunoblotting showed evidence for hK3 protein in neuronal cells. Taken together, our findings support the expression of hK3 in neuronal cells reinforcing the concept of hK3 as a ubiquitous protein with more multifarious biological activity than previously believed. Ongoing research seeks to elucidate the functional significance of hK3 in brain cells.

Aoteaoroa/New Zealand nursing: from eugenics to cultural safety...

The concept of cultural safety offers a unique approach to nursing practice, based on recognition of the power differentials inherent in any interaction. It is from within the context of nursing in Aoteaoroa/New Zealand (A/NZ) that the concept developed and was subsequently integrated into nursing education. Cultural safety is based within a framework of biculturalism, and is congruent with the tenets of the nation's founding document, the Treaty of Waitangi. Clarification of the concept is offered, together with a review of the historical shift in nursing attitudes that has led to the emergence of "cultural safety" as a viable and valued component of nursing practice. The argument is made that cultural safety has allowed for a more reflective, critical understanding of the actions of nursing to develop. This includes recognition that nurses' attitudes and values have inevitably been influenced by social and political forces, and as such are in part reflective of those within the wider community. Comparison between the support given by nurses in the early 1900s to the theory of eugenics and the current acceptance of cultural safety is used to highlight this point. An examination of the literature identifies that ideological and conceptual changes have occurred in the approach of A/NZ nurses to issues with cultural implications for practice. A review of background factors relating to Maori health status and the Treaty of Waitangi is presented as a necessary context to the overall discussion. The discussion concludes with an acknowledgement that while the rhetoric of cultural safety is now part of nursing culture in New Zealand, there is no firm evidence to evaluate its impact in practice. Issues identified as impacting on the ability to assess/research a concept, such as cultural safety, are discussed. For cultural safety to become recognised as a credible (and indispensable) tool, it is necessary to further examine the "end-point" or "outcomes" of the process.