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Search Results: 1 - 10 of 302647 matches for " Sarah J. Kane "
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Age-Related Changes in the Hepatic Pharmacology and Toxicology of Paracetamol
Sarah J. Mitchell,Alice E. Kane,Sarah N. Hilmer
Current Gerontology and Geriatrics Research , 2011, DOI: 10.1155/2011/624156
Abstract: Optimal pharmacotherapy is determined when the pharmacokinetics and pharmacodynamics of the drug are understood. However, the age-related changes in pharmacokinetics and pharmacodynamics, as well as the increased interindividual variation mean optimal dose selection are a challenge for prescribing in older adults. Poor understanding of how hepatic clearance and toxicity are different with age results in suboptimal dose selection, poor efficacy, and/or increased toxicity. Of particular concern is the analgesic paracetamol which has been in use for more than 50 years and is consumed by a large proportion of older adults. Paracetamol is considered to be a relatively safe drug; however, caution must be taken because of its potential for toxicity. Paracetamol-induced liver injury from accidental overdose accounts for up to?55% of cases in older adults. Better understanding of how age affects the hepatic clearance and toxicity of drugs will contribute to evidence-based prescribing for older people, leading to fewer adverse drug reactions without loss of benefit. 1. Introduction Paracetamol remains one of the most studied agents that cause hepatotoxicity due to its clinical relevance and to its dose-dependent hepatotoxicity in animals and humans [1]. Paracetamol is an effective analgesic agent and represents the first-line analgesic therapy for nonmalignant pain [2]. However, the use of paracetamol is limited by its potential to cause hepatotoxicity. With old age, there is an increase in disease for which medications may provide benefit; however, the incidence of serious adverse drug reactions (ADRs) also increases with increasing age, even after controlling for increased medication use [3]. In older adults, most ADRs, including drug-induced liver injury (DILI), are dose-related [4]. Therefore, optimising the safety and efficacy of medication use in older adults is important. For most drugs, the evidence base for dose adjustment in older people is limited to pharmacokinetic studies in small populations of healthy volunteers. There is very little data available on the clinical outcomes of dose adjustment, particularly in the frail aged. In all age groups, an important susceptibility factor for hepatotoxicity is genetic variability [5]. In older people, this may be compounded by the multi-factorial large interindividual variation in response to medications further increasing the risks of toxicity and poor efficacy [5]. This is a particular concern in frailty, a condition of increased vulnerability to adverse events [6]. Although monitoring for clinical response
An Etiological Model of Perfectionism
Gayle K. Maloney, Sarah J. Egan, Robert T. Kane, Clare S. Rees
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0094757
Abstract: Objective Perfectionism has been recognized as a transdiagnostic factor that is relevant to anxiety disorders, eating disorders and depression. Despite the importance of perfectionism in psychopathology to date there has been no empirical test of an etiological model of perfectionism. Method The present study aimed to address the paucity of research on the etiology of perfectionism by developing and testing an etiological model using a sample of 311 clients seeking treatment. Results Structural equation modeling showed a direct relationship between high Parental Expectations and Criticism, and Perfectionism. There was also an indirect relationship between Parental Bonding and Perfectionism that was mediated by core schemas of disconnection and rejection. Finally, it was found that Neuroticism had both an indirect relationship, which was mediated by core schemas, and a direct relationship with perfectionism. Conclusions The study provided the first direct test of an etiological model of perfectionism to date. Clinical implications include investigating whether the inclusion of etiological factors in the understanding and treatment of perfectionism is effective.
Darpp-32 and Its Truncated Variant t-Darpp Have Antagonistic Effects on Breast Cancer Cell Growth and Herceptin Resistance
Long Gu, Sarah Waliany, Susan E. Kane
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006220
Abstract: Background Herceptin (trastuzumab) is a humanized monoclonal antibody that is approved for the treatment of metastatic breast cancer patients whose tumors overexpress Her2 (erbB2/neu). Up to 70% of Her2-positive breast cancers demonstrate a response to Herceptin-based therapies, but resistance almost inevitably arises within a year of the initial response. To help understand the mechanism of Herceptin resistance, we isolated clonal variants of Her2-positive BT474 human breast cancer cells (BT/HerR) that are highly resistant to Herceptin. These cell lines exhibit sustained PI3K/Akt signaling as an essential component of Herceptin-resistant proliferation. Several genes in the protein kinase A (PKA) signaling network have altered expression in BT/HerR cells, including PPP1R1B, which encodes a 32 kDa protein known as Darpp-32 and its amino-terminal truncated variant, t-Darpp. The purpose of the current work was to determine the role of Darpp-32 and t-Darpp in Herceptin resistance. Methodology and Results We determined expression of Darpp-32 and t-Darpp in BT/HerR cells selected for resistance to Herceptin. Subsequently, cDNAs encoding the two isoforms of Darpp-32 were transfected, separately and together, into Her2-positive SK-Br-3 breast cancer cells. Transfected cells were tested for resistance to Herceptin and Herceptin-mediated dephosphorylation of Akt. DNA binding activity by the cAMP response element binding protein (CREB) was also measured. We found that BT/HerR cells overexpressed t-Darpp but not Darpp-32. Moreover, t-Darpp overexpression in SK-Br-3 cells was sufficient for conferring resistance to Herceptin and Herceptin-mediated dephosphorylation of Akt. Darpp-32 co-expression reversed t-Darpp's effects on Herceptin resistance and Akt phosphorylation. t-Darpp overexpression led to increased CREB binding activity, which was also reversible by Darpp-32. Conclusions t-Darpp and Darpp-32 appear to have antagonistic effects on Herceptin resistance. We present a unified model by which these effects might be mediated via the PKA regulatory network.
Balancing the books – a statistical theory of prospective budgets in Earth System science
J. P. O'Kane
Hydrology and Earth System Sciences (HESS) & Discussions (HESSD) , 2003,
Abstract: An honest declaration of the error in a mass, momentum or energy balance, ε, simply raises the question of its acceptability: 'At what value of ε is the attempted balance to be rejected?' Answering this question requires a reference quantity against which to compare ε. This quantity must be a mathematical function of all the data used in making the balance. To deliver this function, a theory grounded in a workable definition of acceptability is essential. A distinction must be drawn between a retrospective balance and a prospective budget in relation to any natural space-filling body. Balances look to the past; budgets look to the future. The theory is built on the application of classical sampling theory to the measurement and closure of a prospective budget. It satisfies R.A. Fisher's 'vital requirement that the actual and physical conduct of experiments should govern the statistical procedure of their interpretation'. It provides a test, which rejects, or fails to reject, the hypothesis that the closing error on the budget, when realised, was due to sampling error only. By increasing the number of measurements, the discrimination of the test can be improved, controlling both the precision and accuracy of the budget and its components. The cost-effective design of such measurement campaigns is discussed briefly. This analysis may also show when campaigns to close a budget on a particular space-filling body are not worth the effort for either scientific or economic reasons. Other approaches, such as those based on stochastic processes, lack this finality, because they fail to distinguish between different types of error in the mismatch between a set of realisations of the process and the measured data. Keywords: balance, budget, sampling, hypothesis test, closing error, Earth System
Amyloid-β and Proinflammatory Cytokines Utilize a Prion Protein-Dependent Pathway to Activate NADPH Oxidase and Induce Cofilin-Actin Rods in Hippocampal Neurons
Keifer P. Walsh, Laurie S. Minamide, Sarah J. Kane, Alisa E. Shaw, David R. Brown, Bruce Pulford, Mark D. Zabel, J. David Lambeth, Thomas B. Kuhn, James R. Bamburg
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0095995
Abstract: Neurites of neurons under acute or chronic stress form bundles of filaments (rods) containing 1:1 cofilin:actin, which impair transport and synaptic function. Rods contain disulfide cross-linked cofilin and are induced by treatments resulting in oxidative stress. Rods form rapidly (5–30 min) in >80% of cultured hippocampal or cortical neurons treated with excitotoxic levels of glutamate or energy depleted (hypoxia/ischemia or mitochondrial inhibitors). In contrast, slow rod formation (50% of maximum response in ~6 h) occurs in a subpopulation (~20%) of hippocampal neurons upon exposure to soluble human amyloid-β dimer/trimer (Aβd/t) at subnanomolar concentrations. Here we show that proinflammatory cytokines (TNFα, IL-1β, IL-6) also induce rods at the same rate and within the same neuronal population as Aβd/t. Neurons from prion (PrPC)-null mice form rods in response to glutamate or antimycin A, but not in response to proinflammatory cytokines or Aβd/t. Two pathways inducing rod formation were confirmed by demonstrating that NADPH-oxidase (NOX) activity is required for prion-dependent rod formation, but not for rods induced by glutamate or energy depletion. Surprisingly, overexpression of PrPC is by itself sufficient to induce rods in over 40% of hippocampal neurons through the NOX-dependent pathway. Persistence of PrPC-dependent rods requires the continuous activity of NOX. Removing inducers or inhibiting NOX activity in cells containing PrPC-dependent rods causes rod disappearance with a half-life of about 36 min. Cofilin-actin rods provide a mechanism for synapse loss bridging the amyloid and cytokine hypotheses for Alzheimer disease, and may explain how functionally diverse Aβ-binding membrane proteins induce synaptic dysfunction.
Long Term Learning, Achievement Tests, and Learner Centered Instruction
Moises Salinas,Sarah Kane-Johnson,Melissa Vasil-Miller
The Journal of Scholarship of Teaching and Learning , 2008,
Abstract:
Optimizing use of 5-ASA in the treatment of ulcerative colitis: Focus on patient compliance and adherence
Steven J Bernick, Sunanda Kane
Patient Related Outcome Measures , 2010, DOI: http://dx.doi.org/10.2147/PROM.S8382
Abstract: imizing use of 5-ASA in the treatment of ulcerative colitis: Focus on patient compliance and adherence Review (3802) Total Article Views Authors: Steven J Bernick, Sunanda Kane Published Date June 2010 Volume 2010:1 Pages 57 - 63 DOI: http://dx.doi.org/10.2147/PROM.S8382 Steven J Bernick1, Sunanda Kane2 1Department of Gastroenterology, Naval Medical Center, San Diego California; 2Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA Abstract: Ulcerative colitis is a chronic condition that requires long-term treatment. The first-line therapy remains 5-ASA, which is available in a variety of different formulations and dosing schedules. Multiple studies have demonstrated that adherence rates to prescribed 5-ASA products is below what would have been expected with significant consequences for important outcomes. Worse disease outcomes, higher medical costs, and even potentially higher rates of colorectal cancer have been associated with nonadherence. Nonadherence is multifactorial, fluid in nature over time, and dependent on disease activity level. Interventions to improve adherence rates have to be individualized. With the advent of simpler dosing regimens it was assumed that adherence rates would improve, but this has not necessarily been the case. Despite our current knowledge about nonadherence, it remains difficult to manage in the long term.
Optimizing use of 5-ASA in the treatment of ulcerative colitis: Focus on patient compliance and adherence
Steven J Bernick,Sunanda Kane
Patient Related Outcome Measures , 2010,
Abstract: Steven J Bernick1, Sunanda Kane21Department of Gastroenterology, Naval Medical Center, San Diego California; 2Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USAAbstract: Ulcerative colitis is a chronic condition that requires long-term treatment. The first-line therapy remains 5-ASA, which is available in a variety of different formulations and dosing schedules. Multiple studies have demonstrated that adherence rates to prescribed 5-ASA products is below what would have been expected with significant consequences for important outcomes. Worse disease outcomes, higher medical costs, and even potentially higher rates of colorectal cancer have been associated with nonadherence. Nonadherence is multifactorial, fluid in nature over time, and dependent on disease activity level. Interventions to improve adherence rates have to be individualized. With the advent of simpler dosing regimens it was assumed that adherence rates would improve, but this has not necessarily been the case. Despite our current knowledge about nonadherence, it remains difficult to manage in the long term.Keywords: ulcerative colitis, adherence, mesalamine, persistence, compliance
A Stopped Negative Binomial Distribution
Michael J. Kane,Daniel Zelterman
Statistics , 2015,
Abstract: This paper introduces a new discrete distribution suggested by curtailed sampling rules common in early-stage clinical trials. We derive the distribution of the smallest number of independent Bernoulli(p) trials needed in order to observe either s successes or t failures. The closed form expression for the distribution as well as the compound distribution are derived. Properties of the distribution are shown and discussed. A case study is presented showing how the distribution can be used to monitor sequential enrollment of clinical trials with binary outcomes as well as providing post-hoc analysis of completed trials.
Characterization of a mesenchymal stem cell line that differentiates to bone and provides niches supporting mouse and human hematopoietic stem cells  [PDF]
Sonal R. Tuljapurkar, John D. Jackson, Susan K. Brusnahan, Barbara J. O’Kane, John G. Sharp
Stem Cell Discovery (SCD) , 2012, DOI: 10.4236/scd.2012.21002
Abstract: Identification of mouse cell lines with properties of primary multipotential mesenchymal stromal cells (MSC) is required to facilitate the use of mouse models for evaluation of mechanisms in bone formation, hematopoiesis and cellular therapies for regenerative medicine. Primary murine MSC vary between strains, are difficult to grow in vitro and have inconsistent properties. The main aim of the study was to establish OMA-AD cells as an appropriate model system to conduct studies on MSC, bone formation and hematopoiesis. OMA-AD cells were isolated by differential trypsinization of C57BL/6J mouse bone marrow (BM) cells. The cells were then repassaged, cloned and characterized. OMA-AD cells were immortal and non-tumorigenic, differentiated readily to all mesenchymal cell types including bone, supported mouse and human hematopoiesis and were immunosuppressive. Our results demonstrated that OMA-AD cells possessed the properties of primary MSC. In addition, these cells grew readily and consistently, thereby facilitating future studies of bone formation, hematopoiesis and mesenchymal cells for regenerative medicine.
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