Medicine and Health Sciences Commons^™

Transitions, Risks, And Actions In Coronary Events--Center For Outcomes Research And Education (Trace-Core): Design And Rationale, Molly Waring, Richard Mcmanus, Jane Saczynski, Milena Anatchkova, David Mcmanus, Randolph Devereaux, Robert Goldberg, Jeroan Allison, Catarina Kiefe

Richard H. McManus

Background: Cardiovascular disease continues to cause significant morbidity, mortality, and impaired quality of life, with unrealized health gains from the underuse of available evidence. The Transitions, Risks, and Actions in Coronary Events Center for Outcomes Research and Education (TRACE-CORE) aims to advance the science of acute coronary syndromes by examining the determinants and outcomes of the quality of transition from hospital to community and by quantifying the impact of potentially modifiable characteristics associated with decreased quality of life, rehospitalization, and mortality. Methods and Results: TRACE-CORE comprises a longitudinal multiracial cohort of patients hospitalized with acute coronary syndromes, 2 research projects, …

Transitions, Risks, And Actions In Coronary Events--Center For Outcomes Research And Education (Trace-Core): Design And Rationale, Molly Waring, Richard Mcmanus, Jane Saczynski, Milena Anatchkova, David Mcmanus, Randolph Devereaux, Robert Goldberg, Jeroan Allison, Catarina Kiefe

Richard H. McManus

Background: Cardiovascular disease continues to cause significant morbidity, mortality, and impaired quality of life, with unrealized health gains from the underuse of available evidence. The Transitions, Risks, and Actions in Coronary Events Center for Outcomes Research and Education (TRACE-CORE) aims to advance the science of acute coronary syndromes by examining the determinants and outcomes of the quality of transition from hospital to community and by quantifying the impact of potentially modifiable characteristics associated with decreased quality of life, rehospitalization, and mortality. Methods and Results: TRACE-CORE comprises a longitudinal multiracial cohort of patients hospitalized with acute coronary syndromes, 2 research projects, …

Diarylheptanoid From Pleuranthodium Racemigerum With In Vitro Prostaglandin E2 Inhibitory And Cytotoxic Activity, Hans Wohlmuth, Myrna Deseo, Don Brushett, Dion Thompson, Graham Macfarlane, Lesley Stevenson, David Leach

Dr Myrna A Deseo

Bioactivity-guided fractionation of an ethanolic extract of the rhizome of Pleuranthodium racemigerum, a tropical Zingiberaceae species from North-eastern Australia, resulted in the isolation and structural elucidation of 1-(4″-methoxyphenyl)-7-(4′-hydroxyphenyl)-(E)-hept-2-ene (1), a new diarylheptanoid related to curcumin. Compound 1 was a fairly potent inhibitor of prostaglandin E2 production in 3T3 murine fibroblasts (IC50 ≈ 34 μM) and also displayed moderate cytotoxicity against this cell line (IC50 = 52.8 μM). The compound also demonstrated cytotoxic activity against the P388D1 murine lymphoblast cell line (IC50 = 117.0 μM) and four human cell lines: Caco-2 colonic adenocarcinoma (IC50 = 44.8 μM), PC3 prostate adenocarcinoma (IC50 …

Prolactin And Fmri Response To Skf38393 In The Baboon, Brad D. Miller, Lauren A. Marks, Jonathan M. Koller, Blake J. Newman, G Larry Bretthorst, Kevin J. Black

Kevin J. Black, MD

Background: This study’s goal was to provide dose-response data for a dopamine agonist in the baboon using standard methods (replicate measurements at each dose, across a range of doses), as a standard against which to subsequently validate a novel pharmacological MRI (phMRI) method. Dependent variables were functional MRI (fMRI) data from brain regions selected a priori, and systemic prolactin release. Necessary first steps included estimating the magnitude and time course of prolactin response to anesthesia alone and to various doses of agonist. These first steps (“time course studies”) were performed with three agonists, and the results were used to select …

Use Of Veterinary Records To Teach Laboratory Thinking Skills In Biology, Christopher Woolverton

Christopher J. Woolverton

No abstract provided.

Development And Characterization Of A Severe Acute Respiratory Syndrome-Associated Coronavirus-Neutralizing Human Monoclonal Antibody That Provides Effective Immunoprophylaxis In Mice, Thomas Greenough, Gregory Babcock, Anjeanette Roberts, Hector Hernandez, William Thomas, Jennifer Coccia, Robert Graziano, Mohan Srinivasan, Israel Lowy, Robert Finberg, Kanta Subbarao, Leatrice Vogel, Mohan Somasundaran, Katherine Luzuriaga, John Sullivan, Donna Ambrosino

William D Thomas Jr

BACKGROUND: Severe acute respiratory syndrome (SARS) remains a significant public health concern after the epidemic in 2003. Human monoclonal antibodies (MAbs) that neutralize SARS-associated coronavirus (SARS-CoV) could provide protection for exposed individuals. METHODS: Transgenic mice with human immunoglobulin genes were immunized with the recombinant major surface (S) glycoprotein ectodomain of SARS-CoV. Epitopes of 2 neutralizing MAbs derived from these mice were mapped and evaluated in a murine model of SARS-CoV infection. RESULTS: Both MAbs bound to S glycoprotein expressed on transfected cells but differed in their ability to block binding of S glycoprotein to Vero E6 cells. Immunoprecipitation analysis revealed …

Treatment With Monoclonal Antibodies Against Clostridium Difficile Toxins, Israel Lowy, Deborah Molrine, Brett Leav, Barbara Blair, Roger Baxter, Dale Gerding, Geoffrey Nichol, William Thomas, Mark Leney, Susan Sloan, Catherine Hay, Donna Ambrosino

William D Thomas Jr

BACKGROUND: New therapies are needed to manage the increasing incidence, severity, and high rate of recurrence of Clostridium difficile infection.

METHODS: We performed a randomized, double-blind, placebo-controlled study of two neutralizing, fully human monoclonal antibodies against C. difficile toxins A (CDA1) and B (CDB1). The antibodies were administered together as a single infusion, each at a dose of 10 mg per kilogram of body weight, in patients with symptomatic C. difficile infection who were receiving either metronidazole or vancomycin. The primary outcome was laboratory-documented recurrence of infection during the 84 days after the administration of monoclonal antibodies or placebo.

RESULTS: …

Human Monoclonal Antibodies Directed Against Toxins A And B Prevent Clostridium Difficile-Induced Mortality In Hamsters, Gregory Babcock, Teresa Broering, Hector Hernandez, Robert Mandell, Katherine Donahue, Naomi Boatright, Anne Stack, Israel Lowy, Robert Graziano, Deborah Molrine, Donna Ambrosino, William Thomas

William D Thomas Jr

Clostridium difficile is the leading cause of nosocomial antibiotic-associated diarrhea, and recent outbreaks of strains with increased virulence underscore the importance of identifying novel approaches to treat and prevent relapse of Clostridium difficile-associated diarrhea (CDAD). CDAD pathology is induced by two exotoxins, toxin A and toxin B, which have been shown to be cytotoxic and, in the case of toxin A, enterotoxic. In this report we describe fully human monoclonal antibodies (HuMAbs) that neutralize these toxins and prevent disease in hamsters. Transgenic mice carrying human immunoglobulin genes were used to isolate HuMAbs that neutralize the cytotoxic effects of either toxin …

Amino Acids 270 To 510 Of The Severe Acute Respiratory Syndrome Coronavirus Spike Protein Are Required For Interaction With Receptor, Gregory Babcock, Diana Esshaki, William Thomas, Donna Ambrosino

William D Thomas Jr

A novel coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), has recently been identified as the causative agent of severe acute respiratory syndrome (SARS). SARS-CoV appears similar to other coronaviruses in both virion structure and genome organization. It is known for other coronaviruses that the spike (S) glycoprotein is required for both viral attachment to permissive cells and for fusion of the viral envelope with the host cell membrane. Here we describe the construction and expression of a soluble codon-optimized SARS-CoV S glycoprotein comprising the first 1,190 amino acids of the native S glycoprotein (S(1190)). The codon-optimized and native S glycoproteins …

Therapy With A Severe Acute Respiratory Syndrome-Associated Coronavirus-Neutralizing Human Monoclonal Antibody Reduces Disease Severity And Viral Burden In Golden Syrian Hamsters, Anjeanette Roberts, William Thomas, Jeannette Guarner, Elaine Lamirande, Gregory Babcock, Thomas Greenough, Leatrice Vogel, Norman Hayes, John Sullivan, Sherif Zaki, Kanta Subbarao, Donna Ambrosino

William D Thomas Jr

BACKGROUND: Immunotherapy with monoclonal antibodies (MAbs) offers safe interventions for the prevention of infection in patients after organ transplantation and for the treatment of cancers and autoimmune diseases. MAb 201 is a severe acute respiratory syndrome-associated coronavirus (SARS-CoV)-specific MAb that prevents establishment of viral replication in vitro and prevents viral replication in vivo when administered prophylactically. The efficacy of MAb 201 in the treatment of SARS was evaluated in golden Syrian hamsters, an animal model that supports SARS-CoV replication to high levels and displays severe pathological changes associated with infection, including pneumonitis and pulmonary consolidation. METHODS: Golden Syrian hamsters that …

Fibre: Male Participants Not Getting Enough, Rebecca Thorne, Jane O'Shea, Qingsheng Zhang, Linda Tapsell, Marijka Batterham, Karen Charlton

Qingsheng Zhang

A regular intake of dietary fibre has been associated with a number of health benefits. Consuming a high fibre diet may significantly lower the risk of developing heart disease, stroke, hypertension, diabetes and obesity (Anderson et al, 2009). Foods high in fibre such as fruit, vegetables, legumes and wholegrains are regularly included in diets targeting weight loss as they are low in fat, sugar and salt and contain a number of vitamins and minerals. Participants in trials using healthy background diets may increase their fibre intake in addition to the study variables. The aim of this study was to report …

Start Date May Predict Attrition 6 Months Into A 12mth Dietary Intervention Weight Loss Trial, Jane O'Shea, Linda Tapsell, Marijka Batterham, Karen Charlton, Yasmine Probst, Rebecca Thorne, Qingsheng Zhang, Holley Jones

Qingsheng Zhang

Participant recruitment is a difficult and time consuming aspect of clinical trials, often resulting in delays and budget overruns. Having reached recruitment targets the next challenge is participant retention. Some weight-loss studies have attrition rates around 60% which may introduce bias in the results. It may be possible to reduce attrition rates if known predictors can be found but to date few studies produced consistent results. The aim of this exploratory study was to determine whether start date could be a predictor of attrition for participants involved in the SMART weight loss clinical trial (ACTRN12608000425392). Recruitment for the trial occurred …

Pork, Beef And Chicken Have Similar Effects On Acute Satiety And Hormonal Markers Of Appetite, Karen Charlton, Linda Tapsell, Marijka Batterham, Rebecca Thorne, Jane O'Shea, Qingsheng Zhang, Eleanor Beck

Qingsheng Zhang

The effects of three different meat-containing breakfast meals (pork, beef or chicken) on acute satiety and appetite regulatory hormones were compared using a within-subjects study design. Thirty fasting non-smoking pre-menopausal women attended a research centre on three test days to consume, a meat-containing meal matched in energy (kJ) and protein content, palatability, and appearance. No difference was found between meat groups for either energy intake or macronutrient profile of food consume data subsequent ad libitum buffet lunch, or over the rest of the day. Visual Analogue Scale(VAS) ratings for hunger and satiety over an 180min period did not differ between …

Cholesterol-Lowering Effects Of B-Glucan Containing Breakfast Cereals And Snack Bars, Karen Charlton, Linda Tapsell, Marijka Batterham, Jane O'Shea, Rebecca Thorne, Qingsheng Zhang, Eleanor Beck

Qingsheng Zhang

No abstract provided.

Cooperative Effects Of Drug-Resistance Mutations In The Flap Region Of Hiv-1 Protease, Jennifer Foulkes-Murzycki, Christina Rosi, Nese Yilmaz, Robert Shafer, Celia Schiffer

Celia A. Schiffer

Understanding the interdependence of multiple mutations in conferring drug resistance is crucial to the development of novel and robust inhibitors. As HIV-1 protease continues to adapt and evade inhibitors while still maintaining the ability to specifically recognize and efficiently cleave its substrates, the problem of drug resistance has become more complicated. Under the selective pressure of therapy, correlated mutations accumulate throughout the enzyme to compromise inhibitor binding, but characterizing their energetic interdependency is not straightforward. A particular drug resistant variant (L10I/G48V/I54V/V82A) displays extreme entropy-enthalpy compensation relative to wild-type enzyme but a similar variant (L10I/G48V/I54A/V82A) does not. Individual mutations of sites …

Gene-Based Therapy For Alpha-1 Antitrypsin Deficiency, Christian Mueller, Terence Flotte

Christian Mueller

Alpha-1 antitrypsin Deficiency (AATD) has been an attractive target for the development of gene therapy because it is a common single gene disorder, for which there would appear to be significant benefit to be gained for lung disease patients by augmentation of plasma levels of wild-type (M) alpha-1 antitrypsin (AAT). While a significant proportion of patients also have liver disease, which is unlikely to be benefitted by augmentation, the potential to treat or prevent lung disease by replacement of plasma levels to at least 11 microMolar (571 mcg/ml) is the basis upon which several protein replacement therapies have been licensed …

Translocation Channel Gating Kinetics Balances Protein Translocation Efficiency With Signal Sequence Recognition Fidelity, Steven Trueman, Elisabet Mandon, Reid Gilmore

Elisabet Mandon

The transition between the closed and open conformations of the Sec61 complex permits nascent protein insertion into the translocation channel. A critical event in this structural transition is the opening of the lateral translocon gate that is formed by four transmembrane (TM) spans (TM2, TM3, TM7, and TM8 in Sec61p) to expose the signal sequence-binding site. To gain mechanistic insight into lateral gate opening, mutations were introduced into a lumenal loop (L7) that connects TM7 and TM8. The sec61 L7 mutants were found to have defects in both the posttranslational and cotranslational translocation pathways due to a kinetic delay in …

Alcohol Facilitates Hcv Rna Replication Via Up-Regulation Of Mir-122 Expression And Inhibition Of Cyclin G1 In Human Hepatoma Cells, Wei Hou, Terence Bukong, Karen Kodys, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND: Clinical studies demonstrate synergistic liver damage by alcohol and hepatitis C virus (HCV); however, the mechanisms by which alcohol promotes HCV infection remain obscure. The liver-specific microRNA-122 (miR-122) regulates HCV replication and expression of host genes, including Cyclin G1. Here, we hypothesized that alcohol regulates miR-122 expression and thereby modulates HCV RNA replication. METHODS: The J6/JFH/Huh-7.5 model of HCV infection was used in this study. Real-time quantitative polymerase chain reaction, Western blotting, electrophoretic mobility shift assay, and confocal microscopy were used for experimental analysis. RESULTS: We found that acute alcohol exposure (25 mM) significantly increased intracellular HCV RNA as …

Structural And Thermodynamic Basis Of Amprenavir/Darunavir And Atazanavir Resistance In Hiv-1 Protease With Mutations At Residue 50, Seema Mittal, Rajintha Bandaranayake, Nancy King, Moses Prabu-Jeyabalan, Madhavi Nalam, Ellen Nalivaika, Nese Yilmaz, Celia Schiffer

Celia A. Schiffer

Drug resistance occurs through a series of subtle changes that maintain substrate recognition but no longer permit inhibitor binding. In HIV-1 protease, mutations at I50 are associated with such subtle changes that confer differential resistance to specific inhibitors. Residue I50 is located at the protease flap tips, closing the active site upon ligand binding. Under selective drug pressure, I50V/L substitutions emerge in patients, compromising drug susceptibility and leading to treatment failure. The I50V substitution is often associated with amprenavir (APV) and darunavir (DRV) resistance, while the I50L substitution is observed in patients failing atazanavir (ATV) therapy. To explain how APV, …

Intersectoral And Interagency Partnerships To Investigate Youth Help-Seeking And The Reponses Of At-Risk Young Men To Intervention Services, Coralie Wilson, Frank Deane, Joseph Ciarrochi

Coralie J Wilson

No abstract provided.

Engaging Young People In Mental Health Services: Overcoming Barriers To Appropriate Help-Seeking., Coralie Wilson, Frank Deane

Coralie J Wilson

No abstract provided.

Online Advertising: Examining The Content And Messages Within Websites Targeted At Children, Lisa Kervin, Sandra Jones, Jessica Mantei

Jessica Mantei

It is recognised that from a young age children spend considerable portions of their leisure time on the Internet. In Australia a number of child-targeted magazines have associated websites, which have high and ever-increasing readership. We do not yet know the impact of this medium upon children. Overt advertising is evident on webpages, but so too are hidden advertisements in the written text, images and games. This material usually does not comply with existing broadcasting codes of practice for mainstream advertising. This article examines the instances of overt and covert advertisements for food within three websites monitored over a 12-month …

The Effects Of Preeclampsia On Signaling To Hematopoietic Progenitor Cells, Donna Santillan, Wendy Hamilton, Ashley Christensen, Katelyn Talcott, Lindsay Gravatt, Mark Santillan, Stephen Hunter

Donna A. Santillan

Background: The role of the microenvironment is important in cell differentiation. The effect of placental disease on the growth and differentiation and hematopoietic stem cells has not been well-studied.

Methods: Enzyme linked immunoassay was used to measure erythropoietin and osteopontin in plasma from umbilical cord blood of children born to normotensive and preeclamptic women. Additionally, CD34+ cells were isolated from umbilical cord blood and grown in complete methylcellulose media. Colony types were identified and enumerated.

Results: Differences in the concentration of erythropoietin in the cord blood between the controls and the preeclamptics approached significance (P = 0.067) using a Mann-Whitney …

Ifn-Gamma Production By Human Natural Killer Cells In Response To Hcv-Infected Hepatoma Cells Is Dependent On Accessory Cells, Shuye Zhang, Banishree Saha, Karen Kodys, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND and AIMS: Interferon-gamma (IFN-gamma), a cytokine produced by activated natural killer cell (NK) and T lymphocytes, is an important regulator of innate and adaptive immunity during hepatitis C virus (HCV) infection. However, the cellular sources and mechanisms of IFN-gamma induction in HCV-infection are not fully understood. METHODS: We cultured normal human peripheral blood mononuclear cells (PBMCs) with different populations of immune cells and JFH-1 HCV-infected Huh7.5 (JFH-1/Huh7.5) cells. RESULTS: We found that PBMCs produced large amounts of IFN-gamma after co-culture with JFH-1/Huh7.5 cells. Using intracellular cytokine staining we confirmed that NK cells and NKT cells (to a lesser extent) …

Micrornas In Liver Disease, Gyongyi Szabo, Shashi Bala

Gyongyi Szabo

Small, noncoding microRNAs (miRNAs) regulate diverse biological functions in the liver and increasing evidence suggests that they have a role in liver pathology. This Review summarizes advances in the field of miRNAs in liver diseases, inflammation and cirrhosis. MicroRNA-122, the most abundant miRNA in hepatocytes, has well-defined roles in HCV replication, and data indicate that it also serves as a viable therapeutic target. The role of miR-122 is also emerging in other liver diseases. Ample evidence exists for the important regulatory potential of other miRNAs in conditions associated with liver inflammation related to alcohol use, the metabolic syndrome or autoimmune …

Preventing Paediatric Obesity; Recommendations From A Community-Based Qualitative Investigation, Patricia Tucker, Jennifer Irwin, L. Sangster Bouck, Meizi He, G. Pollett

Trish Tucker

Childhood obesity is on the rise, and interventions targeted at pre-school-aged children are essential for the primary prevention of this disease. Physical activity programming and decreasing screen viewing may be advantageous ways to reduce the early onset of obesity. Parents' perceptions regarding effective tools and programmes to target obesity are needed to develop an efficacious programme. Ten semi-structured focus groups were conducted for this qualitative study. Two experienced moderators facilitated all focus groups which were conducted in local day cares, workplaces and play groups, frequented by parents. All focus groups were audio-recorded and transcribed verbatim. Strategies to ensure trustworthiness of …

Healthy Eating And Physical Activity Challenges And Opportunities In After-School Programs: Providers’ Perspectives, Heather Thomas, L. Fellner, Patricia Tucker, Jennifer Irwin

Trish Tucker

The purpose of this study was to understand after-school program providers’ perspectives of (a) current physical activity and nutrition curriculum, practices, and challenges, and (b) necessary modifications, program suggestions or resource needs to improve the healthy eating and active living practices within their after-school program for children aged 6 to 12 years. This qualitative study targeted a sample of nine after-school program providers in London, Ontario. Data was collected via in-depth interviews and a demographic survey between January and April 2009. Strategies to enhance data trustworthiness were incorporated throughout. After-school program providers identified insufficient healthy eating curriculum and requested interactive, …

Human Monoclonal Antibody Mbl-Hcv1 Delays Hcv Viral Rebound Following Liver Transplantation: A Randomized Controlled Study, R. Chung, F. Gordon, M. Curry, T. Schiano, S. Emre, K. Corey, J. Markmann, M. Hertl, J. Pomposelli, E. Pomfret, S. Florman, M. Schilsky, Teresa Broering, Robert Finberg, Gyongyi Szabo, Phillip Zamore, U. Khettry, Gregory Babcock, Donna Ambrosino, Brett Leav, Mark Leney, H. Smith, Deborah Molrine

Gyongyi Szabo

Rapid allograft infection complicates liver transplantation (LT) in patients with hepatitis C virus (HCV). Pegylated interferon-alpha and ribavirin therapy after LT has significant toxicity and limited efficacy. The effect of a human monoclonal antibody targeting the HCV E2 glycoprotein (MBL-HCV1) on viral clearance was examined in a randomized, double-blind, placebo-controlled pilot study in patients infected with HCV genotype 1a undergoing LT. Subjects received 11 infusions of 50 mg/kg MBL-HCV1 (n=6) or placebo (n=5) intravenously with three infusions on day of transplant, a single infusion on days 1 through 7 and one infusion on day 14 after LT. MBL-HCV1 was well-tolerated …

Dietary Methodology In Clinical Trials: Changing Dietary Fat Profiles, Linda Tapsell, Jane O'Shea, Marijka Batterham, Karen Charlton

Karen E. Charlton

No abstract provided.

Fibre: Male Participants Not Getting Enough, Rebecca Thorne, Jane O'Shea, Qingsheng Zhang, Linda Tapsell, Marijka Batterham, Karen Charlton

Karen E. Charlton

A regular intake of dietary fibre has been associated with a number of health benefits. Consuming a high fibre diet may significantly lower the risk of developing heart disease, stroke, hypertension, diabetes and obesity (Anderson et al, 2009). Foods high in fibre such as fruit, vegetables, legumes and wholegrains are regularly included in diets targeting weight loss as they are low in fat, sugar and salt and contain a number of vitamins and minerals. Participants in trials using healthy background diets may increase their fibre intake in addition to the study variables. The aim of this study was to report …