A Correlational Study Exploring Nurse Work Anxiety and Animal-Assisted Therapy.

OBJECTIVE: The aim of this study was to perform a correlational study to explore nurse work anxiety. BACKGROUND: Nurses experience work anxiety with chronic stressful situations, high-acuity assignments, and rigorous patient care standards. The purpose of this study was to determine whether animal-assisted therapy during active worked hours would reduce nurse work-related anxiety. METHODS: Animal-assisted therapy interventions were performed for both day and night shifts. Beck's Anxiety Inventory (BAI) tool was used pre and post intervention. Each nurse interacted with the therapy dog for at least 10 minutes. RESULTS: Pet-assisted therapy as an intervention for nurses during work reduced work-related anxiety (t = 5.878, P < 0.05). A Pearson's correlational study displayed a strong positive correlation between the animal-assisted therapy and reduction in BAI scores (r = 0.7717, R2 = 0.5955). CONCLUSION: This prospective study has shown that nurse work anxiety significantly decreased during worked hours of active bedside care when the nurses actively engaged with a therapy dog.

Design, synthesis, and evaluation of imidazo[4,5-c]pyridin-4-one derivatives with dual activity at angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-γ.

Identification of a series of imidazo[4,5-c]pyridin-4-one derivatives that act as dual angiotensin II type 1 (AT1) receptor antagonists and peroxisome proliferator-activated receptor-γ (PPARγ) partial agonists is described. Starting from a known AT1 antagonist template, conformational restriction was introduced by incorporation of an indane ring that when combined with appropriate substitution at the imidazo[4,5-c]pyridin-4-one provided novel series 5 possessing the desired dual activity. The mode of interaction of this series with PPARγ was corroborated through the X-ray crystal structure of 12b bound to the human PPARγ ligand binding domain. Modulation of activity at both receptors through substitution at the pyridone nitrogen led to the identification of potent dual AT1 antagonists/PPARγ partial agonists. Among them, 21b was identified possessing potent dual pharmacology (AT1 IC(50) = 7 nM; PPARγ EC(50) = 295 nM, 27% max) and good ADME properties.

The role of the dually certified primary care/psychiatric mental health nurse practitioner in treating high-needs/high-cost patients.

ABSTRACT: National nursing organizations have called for nurses to provide leadership in care solutions for high-cost/high-needs vulnerable populations. In response to this call, important modifications are emerging in Doctor of Nursing Practice programs, including an increasing number of nurses pursuing dual certification in primary care and psychiatric mental health or primary care nurse practitioners returning for a postgraduate certificate in psychiatric mental health. This innovative role warrants examination, particularly because it relates to high-needs/high-cost patients such as those with serious mental illness (SMI). This article highlights two aspects of the role of the primary care/psychiatric mental health nurse practitioner (PC/PMHNP): one, to provide a vision of the PC/PMHNP as a unique solution for optimal care of vulnerable patients and two, to demonstrate potential contributions of the PC/PMHNP to the larger health care system. A case exemplar is used to illustrate role contributions of the PC/PMHNP in a high-needs/high-cost patient with SMI and complex co-occurring physical illness. Three capacities of the PC/PMHNP are discussed: depth and breath, expert engagement and rapport building, and full patient-centered care and flexibility. The case exemplar emphasizes the PC/PMHNP value through transitions across care settings and where gaps in service frequently occur. The impact of the PC/PMHNP on improved patient outcomes, patient and provider satisfaction, and cost savings are explored.

ICF classification of therapeutic goals for outpatient episodes of neurorehabilitation in post-stroke and Parkinson disease.

PURPOSE: To understand therapeutic priorities, a secondary data analysis on a retrospective cohort was conducted to classify rehabilitation goals according to the International Classification of Functioning, Disability, and Health (ICF). MATERIALS AND METHODS: Therapeutic goals from an initial outpatient physical or occupational therapy evaluation for patients post-stroke or with Parkinson disease, were classified into Level 1 of the ICF. Goals in the Activity and Participation component were further sub-classified as activity capacity or activity performance (self-report or direct) in daily life. RESULTS: 776 goals across 104 participants were classified into Level 1 of the ICF. The majority, 73% (563/776) were classified as Activity and Participation, 20% (155/776) as Body Function and 2% (17/776) as Environmental Factors. Fifty-two percent (400/776) of all goals were classified as activity capacity and 21% (163/776) as activity performance in daily life, with 21% (160/776) of goals measuring self-report activity performance in daily life and less than 1% (3/776) of goals measuring direct activity performance in daily life. CONCLUSIONS: While the majority of therapeutic goals were classified into the Activity and Participation component, less than 1% of goals measured direct activity performance in daily life. If people seek outpatient rehabilitation to improve functioning in their real-world environment, therapeutic goal setting should reflect this.

The majority of therapeutic goals for an episode of outpatient neurorehabilitation were classified into the Activity and Participation component of the International Classification of Functioning, Disability, and Health.However, less than 1% of therapeutic goals measured direct activity performance in daily life.If people with neurological diagnoses seek out outpatient rehabilitation to improve functioning in their real-world environment, than therapeutic goal setting should reflect this.

Cerebrospinal fluid cytokine dynamics differ between Alzheimer disease patients and elderly controls.

The time courses of levels of multiple plasma and cerebrospinal fluid (CSF) cytokines in patients with Alzheimer disease (AD) and in age-matched control subjects were compared. Interleukin (IL)-1ß, IL-2, IL-6, IL-8, IL-10, IL-12p70, granulocyte-macrophage colony-stimulating factor, interferon-γ, and tumor necrosis factor alpha levels were measured 7 times over a 24-hour period in plasma and CSF using a lumbar catheter. Baseline plasma and CSF cytokine levels were found to be similar in AD and control subjects. However, the CSF levels of all measured cytokines, except IL-6 and IL-8, diverged over time between AD and control subjects, such that CSF cytokine levels in AD subjects were higher than in controls. This difference was greatest at 24 hours after the insertion of the lumbar catheter. In contrast, no differences in cytokine trajectories were seen in plasma. These data suggest that the neuroinflammatory response to lumbar catheter placement differs between AD and control subjects.

Effect of human cerebrospinal fluid sampling frequency on amyloid-ß levels.

BACKGROUND: ß-amyloid peptide (Aß) is associated with neurodegeneration in Alzheimer's disease. Emerging evidence indicates that Aß levels in cerebrospinal fluid (CSF) may serve as an early clinical biomarker for evaluating pharmacological activity of new drug candidates targeting Aß production or Aß clearance. Therefore, it is critical to understand whether intrasubject levels of CSF Aß are consistent between sampling intervals to determine whether Aß can be used as a pharmacodynamic biomarker for drug candidates. Previous studies have produced seemingly conflicting observations for the intrasubject stability of CSF Aß levels; we attempt to reconcile these conflicting observations. METHODS: The current study examined the Aß levels in CSF collected with various sampling frequencies from three clinical studies conducted in healthy young or elderly subjects at the same investigative site for the purpose of designing future studies. RESULTS: The results suggest that CSF sampling frequency and/or sampling volume contributes to intrasubject variability in CSF Aß levels, and that lowering the CSF sampling frequency may help minimize this effect. CONCLUSION: These results will help guide clinical trial design for Alzheimer's disease therapy.

Development of a Medication Management Program in Permanent Supportive Housing.

We describe a nurse-led project that aimed to assist a permanent supportive housing facility for chronically homeless individuals to improve medication adherence by refining a medication management program. Client and staff engagement through needs assessment, feedback, and evaluation formed the foundation for a sustainable medication management program.

Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor.

Signaling through the erbB receptor family of tyrosine kinases contributes to the proliferation, differentiation, migration, and survival of a variety of cell types. Abnormalities in members of this receptor family have been shown to play a role in oncogenesis, thus making them attractive targets for anticancer treatments. PF-00299804 is a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor currently in phase I clinical trials. PF-00299804 is believed to irreversibly inhibit erbB tyrosine kinase activity through binding at the ATP site and covalent modification of nucleophilic cysteine residues in the catalytic domains of erbB family members. Oral administration of PF-00299804 causes significant antitumor activity, including marked tumor regressions in a variety of human tumor xenograft models that express and/or overexpress erbB family members or contain the double mutation (L858R/T790M) in erbB1 (EGFR) associated with resistance to gefitinib and erlotinib. Furthermore, PF-00299804 shows exceptional distribution to human tumor xenografts and excellent pharmacokinetic properties across species.

Tyrosine Kinase Inhibitors. 20. Optimization of Substituted Quinazoline and Pyrido[3,4-d]pyrimidine Derivatives as Orally Active, Irreversible Inhibitors of the Epidermal Growth Factor Receptor Family.

Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were determined to provide rapid inhibition of cellular erbB1 autophosphorylation and good metabolic stability in liver microsome and hepatocyte assays. The influence of 4-anilino substitution on pan-erbB inhibitory potency was investigated. Several anilines were identified as providing potent, reversible pan-erbB inhibition. Optimum 4- and 6-substituents with known 7-substituents provided preferred irreversible inhibitors for pharmacodynamic testing in vivo. Quinazoline 54 and pyrido[3,4-d]pyrimidine 71 were identified as clearly superior to canertinib. Both compounds possess a piperidinyl crotonamide Michael acceptor and a 3-chloro-4-fluoroaniline, indicating these as optimized 6- and 4-substituents, respectively. Pharmacokinetic comparison of compounds 54 and 71 across three species selected compound 54 as the preferred candidate. Compound 54 (PF-00299804) has been assigned the nomenclature of dacomitinib and is currently under clinical evaluation.

The Relationship between Different Assays for Detection and Quantification of Amyloid Beta 42 in Human Cerebrospinal Fluid.

Alzheimer's disease (AD), which is characterized by a degeneration of neurons and their synapses, is one of the most common forms of dementia. CSF levels of amyloid ß(42) (Aß(42)) have been recognized as a strong candidate to serve as an AD biomarker. There are a number of commercial assays that are routinely employed for measuring Aß(42); however, these assays give diverse ranges for the absolute levels of CSF Aß(42). In order to employ CSF Aß(42) as a biomarker across multiple laboratories, studies need to be performed to understand the relationship between the different platforms. We have analyzed CSF samples from both diseased and nondiseased subjects with two different widely used assay platforms. The results showed that different values for the levels of CSF Aß(42) were reported, depending on the assay used. Nonetheless, both assays clearly demonstrated statistically significant differences in the levels of Aß(42) in CSF from AD relative to age-matched controls (AMC). This paper provides essential data for establishing the relationship between these assays and provides an important step towards the validation of Aß(42) as a biomarker for AD.

Discovery of a series of imidazo[4,5-b]pyridines with dual activity at angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-γ.

Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-γ (PPARγ) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPARγ confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPARγ activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC(50) = 1.6 nM) with partial PPARγ agonism (EC(50) = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.

Comparing levels of biochemical markers in CSF from cannulated and non-cannulated rats.

Cerebrospinal fluid (CSF) is commonly used for assessing biomarkers of drug efficacy or disease progression in the central nervous system. Studies of CSF from pre-clinical species can characterize biomarkers for use in clinical trials. However, obtaining CSF from pre-clinical species, particularly rodents, can be challenging due to small body sizes, and consequently, low volumes of CSF. Surgical cannulation of rats is commonly used to allow for CSF withdrawal from the cisterna magna. However, cannulae do not remain patent over multiple days, making chronic studies on the same rats difficult. Moreover, CSF biomarkers may be affected by cannulation. Thus cannulation may contribute confounding factors to the understanding of CSF biomarkers. To determine the potential impact on biomarkers, CSF was analyzed from cannulated rats, surgically implanted with catheters as well as from non-cannulated rats. Brain protein biomarkers (αII-spectrin SBDP150 and total tau) and albumin, were measured in the CSF using ELISA assays. Overall, cannulated rat CSF had elevated levels of the biomarkers examined compared to non-cannulated rat CSF. Additionally, the variation in biomarker levels observed among CSF from cannulated rats was greater than that observed for non-cannulated rat CSF. These results demonstrate that in some cases, biomarker assessment using CSF from cannulated rats may differ from that of non-cannulated animals and may contribute confounding factors to biomarker measurements and assay development for clinical use.

Mice expressing the Swedish APP mutation on a 129 genetic background demonstrate consistent behavioral deficits and pathological markers of Alzheimer's disease.

Mutant Tg2576 mice which possess the human "Swedish" APP mutation have been shown to demonstrate both Abeta plaque pathology and memory deficits in behavioral tasks. These mice are routinely maintained on a mixed C57BL/6xSJL genetic background which exhibits a high frequency of retinal degeneration allele and high variability in many behavioral assays. The same APP mutation is also available maintained on a 129 genetic background, providing more genetic homogeneity, but little data are published regarding the effects of the mutation on this background. We investigated whether transgenic mice expressing the Swedish mutation on the 129 background show similar behavioral deficits and Abeta pathology as those on the mixed background. Mice on the 129 background were tested at 6-7, 11-12, or 18-19 months of age in locomotor activity, Y-maze spontaneous alternation, and contextual fear conditioning. Differences were detected between WT and Tg mice in locomotor activity at 6-7 and 18-19 months, Y-maze at 6-7 and 11-12 months, and fear conditioning at 6-7, 11-12, and 18-19 months. In contrast, Tg mice on the mixed B6/SJL background tested at 6-7 months only demonstrated significant impairment in the contextual fear conditioning assay and in the Y-maze in one of 2 cohorts tested. Despite the behavioral differences observed, similar Abeta pathology was observed between Tg mice on the two genetic backgrounds. These results indicate that mice on the 129 genetic background may generate more consistent and robust behavioral differences, providing a useful model for testing therapeutic agents for Alzheimer's disease.