Biomedical subjects

Mary Beth Thomas

Publications and source records attributed to Mary Beth Thomas.

9 recordsLinked to original sources

PubMed2006

Cardiac glycosides provide neuroprotection against ischemic stroke: discovery by a brain slice-based compound screening platform.

We report here the results of a chemical genetic screen using small molecules with known pharmacologies coupled with a cortical brain slice-based model for ischemic stroke. We identified a small-molecule compound not previously appreciated to have neuroprotective action in ischemic stroke, the cardiac glycoside neriifolin, and demonstrated that its properties in the brain slice assay included delayed therapeutic potential exceeding 6 h. Neriifolin is structurally related to the digitalis class of cardiac glycosides, and its putative target is the Na(+)/K(+)-ATPase. Other cardiac glycoside compounds tested also showed neuroprotective activity, although with lower apparent potencies. In subsequent whole-animal studies, we found that neriifolin provided significant neuroprotection in a neonatal model of hypoxia/ischemia and in a middle cerebral artery occlusion model of transient focal ischemia. The neuroprotective potential of Na(+)/K(+)-ATPase is of particular interest because of its known "druggability"; indeed, Food and Drug Administration-approved, small-molecule compounds such as digitoxin and digoxin have been in clinical usage for congestive heart failure and arrhythmias for several decades. Thus, an existing cardiac glycoside or closely related compound could provide an accelerated path toward clinical trial testing for ischemic stroke. Our findings underscore the important role that hypothesis-neutral, high-content, tissue-based screens can play in the identification of new candidate drugs and drug targets for the treatment of diseases for which validated therapeutic pathways are not currently available.

Aging↗

PubMed2005

Inhibition of p53 by lentiviral mediated shRNA abrogates G1 arrest and apoptosis in retinal pigmented epithelial cell line.

We silenced p53 gene expression in ARPE-19, a human retinal pigmented epithelial cell line using RNA interference. The effect of silencing the p53 gene in proliferating ARPE-19 cells was studied. Four short hairpin RNAs (shRNAs) targeting different regions of human p53 mRNA were delivered individually into ARPE-19 cells using lentiviral vector to produce stable cell lines. p53 mRNA and protein levels were reduced to varying extents in the four shRNA-transduced ARPE-19 cell lines. The cell line that showed greatest reduction (85-90%) of p53 expression showed decreased p21 promoter activation after DNA damage with camptothecin, etoposide and MMS. Whereas treatment of wild type ARPE-19 cells with camptothecin resulted in apoptosis, silencing p53 expression increased their survival. Cell cycle analyses indicated that irradiation resulted in a G(1) arrest in ARPE-19 cells, and that the arrest was significantly reduced in p53-silenced cells. Thus, p53 plays a central role in the response of ARPE-19 cells to DNA damaging agents that act via different mechanisms. Additionally, ARPE-19 cells with reduced p53 expression behave similar to tumor cell lines with mutated or non-functional p53. The present data demonstrate the utility of lentiviral vectors to create stable isogenic cell lines with reduced expression of a specific gene, thereby permitting the study of the function of a gene, the pathways controlled by it, and the effect of therapeutics on a cell with altered genetic makeup in a pair-wise fashion.

Apoptosis↗

PubMed2005

Thought for application and application with thought: issues in theoretical thinking and practical wisdom.

Both theoretical thinking and practical wisdom are used by health professionals in their clinical practice. Lately, discussion has centered on the abstract phrase "theory-practice gap." The health profession is not the only discipline that seeks unity in theory and practice issues. Education is also building bridges in this arena. One reoccurring myth is the notion that theory and practice are separate; as a result, this gives a mistaken impression that theory serves no purpose in practice. Discussion of the issues in this paper includes definitions of theoretical thinking and practical wisdom, theoretical and practical knowledge development, and relevance to health professional's education, practice and science. These issues must be communicated to practitioners, educators and theorists. A collective definition to begin communication is proposed and suggestions are offered for addressing key issues.

Health Knowledge, Attitudes, Practice↗

PubMed2005

Lentiviral vector-based models of amyloid pathology: from cells to animals.

Lentiviral vectors are efficient tools for the introduction of genes into a wide range of established and primary cells in vitro, ex vivo, and in vivo, and also permit efficient transgenesis in a wide range of mammalian species. Our goals have been to apply the broad capabilities of the lentiviral vector system to AD research. Using a set of vectors expressing APP and PS1 genes, we demonstrated the efficiency and fidelity of the system for in vitro biochemical analyses of genes and pathways involved in plaque deposition. These analyses were performed in cell lines and in primary neuronal cultures, which have previously been difficult to use. The methods and tools described here are applicable to the study of effects of other genes and gene combinations on APP processing, including suppression of gene activity by delivering shRNAs. We have attempted to create local plaque pathology by stereotactic injection of APP and PS1 expressing vectors into mouse brains for use as a rapid model for plaque pathology that can be used in a broad range of mammals. No amyloid or preamyloid pathology has been detected over a six-month period; the possible reasons are discussed. Lastly, we have used the vectors to create transgenic rats expressing mutant APP and mutant PS1 and have obtained the first set of positive pups with more expected. The results presented here demonstrate the utility of Lentiviral vector-based approaches to the study of AD and other neurodegenerative diseases.

Amyloid beta-Protein Precursor↗

PubMed2004

Ultrastructure of the calcium-sequestering gastrodermal cell in the hydroid Hydractinia symbiolongicarpus (Cnidaria, Hydrozoa).

Large, free-floating crystals of calcium carbonate occur in vacuoles of gastrodermal cells of the hydroid Hydractinia symbiolongicarpus. Here, morphological details about the process by which these cells accumulate and sequester calcium are provided by a cytochemical method designed to demonstrate calcium at the ultrastructural level. Electron-dense material presumably indicative of the presence of calcium was EGTA-sensitive and was shown by parallel electron energy loss spectroscopy (EELS) and energy spectroscopic imaging (ESI) to contain calcium. Calcium occurred in only one cell type, the endodermally derived gastrodermal cell. In these cells, the electron-dense material appeared first as a fine precipitate in the cytosol and nucleus and later as larger deposits and aggregates in the vacuole. During the life cycle, gastrodermal cells of the uninduced planula and the planula during metamorphic induction sequestered calcium. In primary polyps and polyps from established colonies, gastrodermal cells sequestered calcium, but the endodermal secretory cells did not. Our observations support the hypothesis that gastrodermal cells function as a physiological sink for calcium that enters the organism in conjunction with calcium-requiring processes such as motility, secretion, and metamorphosis.

Animals↗

PubMed2004

Novel approaches to models of Alzheimer's disease pathology for drug screening and development.

Development of therapeutics for Alzheimer's disease (AD) requires appropriate cell culture models that reflect the errant biochemical pathways and animal models that reflect the pathological hallmarks of the disease as well as the clinical manifestations. In the past two decades AD research has benefited significantly from the use of genetically engineered cell lines expressing components of the amyloid-generating pathway, as well as from the study of transgenic mice that develop the pathological hallmarks of the disease, mainly neuritic plaques. The choice of certain cell types and the choice of mouse as the model organism have been mandated by the feasibility of introduction and expression of foreign genes into these model systems. We describe a universal and efficient gene-delivery system, using lentiviral vectors, that permits the development of relevant cell biological systems using neuronal cells, including primary neurons and animal models in mammalian species best suited for the study of AD. In addition, lentiviral gene delivery provides avenues for creation of novel models by direct and prolonged expression of genes in the brain in any vertebrate animal. TranzVector is a lentiviral vector optimized for efficiency and safety that delivers genes to cells in culture, in tissue explants, and in live animals regardless of the dividing or differentiated status of the cells. Genes can also be delivered efficiently to fertilized single-cell-stage embryos of a wide range of mammalian species, broadening the range of the model organism (from rats to nonhuman primates) for the study of disease mechanism as well as for development of therapeutics.

Alzheimer Disease↗

PubMedDate not supplied

Theoretical approaches for investigating patient safety.

Patient safety and freedom from accidental injury is an issue that is promoting the search for excellence among healthcare providers, payers, and consumers. The issue is complex and multifaceted, providing many avenues for analysis, quality enhancement, and research. Several models exist that may assist in exploring patient safety issues and the relationships between error and safety. Three models are discussed and research questions are generated that with further investigation will help us to understand the complexity of error management and the promotion of patient safety. Because of their leadership role and guardianship in managing patient care, clinical nurse specialists understand and promote models that improve safety for their patients.

Ergonomics↗

PubMedDate not supplied

Palliative care: rapid redesign to support systemwide quality improvement.

Large-scale change techniques and rapid redesign methodologies were used to improve the quality of care delivered to patients at the end of life in a large, multihospital healthcare delivery system. By bringing key stakeholders from across the system together at a symposium to formulate the vision and critical criteria for palliative care programs, as well as to develop a flexible set of design tools, each region in the system could respond to the unique needs of its own community. Hospice length of stay for the system improved by 100% in the year after the systemwide symposium.

Catholicism↗

PubMedDate not supplied

Regulatory compliance issues in behavioral health.

Behavioral health as a discipline has grappled with regulatory compliance issues on its own, tending to be isolated from other specialties and to benefit little from the mistakes and solutions of the rest of medicine. The most common problems with behavioral health regulatory compliance have to do with documentation, billing and coding, treatment plans, and medical necessity. Regulatory compliance is inextricably linked to quality of care. Providers can assess their compliance efforts by asking themselves a series of questions and, most important, by assessing the quality of the care they provide. Sound research and outcomes-based practice are the best ways to improve outcomes in behavioral health treatment and will be the most effective methods for aligning practice with regulations.

Education, Continuing↗