Medical Sciences Commons^™

Clinical Trials In Alzheimer Disease: Debate On The Use Of Placebo Controls, Peter J. Whitehouse

Faculty Scholarship

During the past 10 years, there has been a rapidly growing number of pharmaceutical industry-sponsored drug trials for treatment of Alzheimer disease (AD) and other neurodegenerative diseases. As public awareness and concerns about AD have grown, so has interest in developing drug therapies for retarding symptom progression, delaying onset, and ultimately curing the disease. Ethical debate on the use of placebo control trials in AD research has come of age in the United States with the availability of treatments approved by the Food and Drug Administration. The experts and the public agree that more effective therapies are necessary, and new …

Dichotomy Between Naïve And Memory Cd4+ T Cell Responses To Fas Engagement, J. Desbarats, T. Wade, W. F. Wade, M. K. Newell

Dartmouth Scholarship

Engagement of Fas (APO-1, CD95), a member of the tumor necrosis factor receptor superfamily, can induce apoptotic cell death. However, Fas engagement also can costimulate lymphocyte proliferation. The physiologic regulation of these two outcomes is poorly understood. Here, we have used two systems, the first in vitro and the second in vivo, to demonstrate that naïve and memory CD4+ T cells display dichotomous responses to Fas ligation. Naïve CD4+ T cells (CD44lo, CD45RB+, CD62L+) die as a consequence of Fas ligation in the presence of anti-CD3 antibody, whereas memory T cells (CD44hi, CD45RB−, CD62L−), freshly isolated from the same …

Core-Binding Factor Influences The Disease Specificity Of Moloney Murine Leukemia Virus, Amy F. Lewis, Terryl Stacy, William R. Green, Lekidelu Taddesse-Heath, Janet W. Hartley, Nancy A. Speck

Dartmouth Scholarship

The core site in the Moloney murine leukemia virus (Moloney MLV) enhancer was previously shown to be an important determinant of the T-cell disease specificity of the virus. Mutation of the core site resulted in a significant shift in disease specificity of the Moloney virus from T-cell leukemia to erythroleukemia. We and others have since determined that a protein that binds the core site, one of the core-binding factors (CBF) is highly expressed in thymus and is essential for hematopoiesis. Here we test the hypothesis that CBF plays a critical role in mediating pathogenesis of Moloney MLV in vivo. We …

A Vibrio Cholerae Lysr Homolog, Aphb, Cooperates With Apha At The Tcpph Promoter To Activate Expression Of The Toxr Virulence Cascade, Gabriela Kovacikova, Karen Skorupski

Dartmouth Scholarship

We describe here a new member of the LysR family of transcriptional regulators, AphB, which is required for activation of the Vibrio cholerae ToxR virulence cascade. AphB activates the transcription of the tcpPH operon in response to environmental stimuli, and this process requires cooperation with a second protein, AphA. The expression of neither aphA or aphB is strongly regulated by environmental stimuli, raising the possibility that the activities of the proteins themselves may be influenced under various conditions. Strains of the El Tor biotype of V. cholerae typically exhibit lower expression of ToxR-regulated virulence genes in vitro than classical strains …

Three V-Snares And Two T-Snares, Present In A Pentameric Cis-Snare Complex On Isolated Vacuoles, Are Essential For Homotypic Fusion, Christian Ungermann, Gabriele F. Von Mollard, Ole N. Jensen, Nathan Margolis, Tom H. Stevens, William Wickner

Dartmouth Scholarship

Vacuole SNAREs, including the t-SNAREs Vam3p and Vam7p and the v-SNARE Nyv1p, are found in a multisubunit "cis" complex on isolated organelles. We now identify the v-SNAREs Vti1p and Ykt6p by mass spectrometry as additional components of the immunoisolated vacuolar SNARE complex. Immunodepletion of detergent extracts with anti-Vti1p removes all the Ykt6p that is in a complex with Vam3p, immunodepletion with anti-Ykt6p removes all the Vti1p that is complexed with Vam3p, and immunodepletion with anti-Nyv1p removes all the Ykt6p in complex with other SNAREs, demonstrating that they are all together in the same cis multi-SNARE complex. After priming, which disassembles …

Interaction Between Fgf And Bmp Signaling Pathways Regulates Development Of Metanephric Mesenchyme., Andrew T. Dudley, R. E. Godin, E. J. Robertson

Journal Articles: Genetics, Cell Biology & Anatomy

Nephrogenesis in the mouse kidney begins at embryonic day 11 and ends approximately 10 days postpartum. During this period, new nephrons are continually being generated from a stem-cell population-the nephrogenic mesenchyme-in response to signals emanating from the tips of the branching ureter. Relatively little is known about the mechanism by which the nephrogenic mesenchyme cell population is maintained at the tips of the ureter in the presence of signals promoting tubulogenesis. Previous studies have shown that a loss of Bmp7 function leads to kidney defects that are a likely result of progressive loss of nephrogenic mesenchyme by apoptosis. The studies …

Characterizing Erythrocyte Motions In Flowing Blood, Markos Leggas

Theses and Dissertations (ETD)

Characterizing the probabilistic motions of cells is a prerequisite for the development of a general model of transport and surface deposition of white cells and platelets (WBC/P). These phenomena differ greatly when red blood cells (RBC) are present at normal levels, but follow convective diffusion in dilute suspensions. A critical need is to understand and characterize dispersion and diffusion as they apply to red cells in suspension flow. The dispersive motions of
0.5-micrometer beads and fluorescently labeled human RBC flowing in dilute (0.003%) and concentrated (25%) RBC suspensions, respectively, were characterized using fluorescence videomicroscopy methods, and times for individual tracer …

Insertional Inactivation Of Treponema Denticola Tap1 Results In A Nonmotile Mutant With Elongated Flagellar Hooks, Ronald J. Limberger, Linda L. Slivienski, Jacques Izard, William A. Samsonoff

Department of Food Science and Technology: Faculty Publications

The treponemal fla operon is comprised of numerous motility-related genes; however, the initial gene of this operon, tap1, has no known function. A recently developed system to generate specific mutants in Treponema denticola was utilized to determine if Tap1 was essential for motility. T. denticola tap1 and flanking DNA were identified, cloned, and sequenced, and a suicide plasmid that contained tap1 interrupted with an erythromycin resistance cassette (ermF and ermAM) was constructed. Because of potential polar effects from this cassette, a second plasmid that contained tap1 interrupted with a modified erythromycin resistance cassette that lacked the putative ermF transcription …

Interruption Of Multiple Cellular Processes In Ht-29 Epithelial Cells By Pseudomonas Aeruginosa Exoenzyme S, Joan C. Olson, Jennifer E. Fraylick, Eileen M. Mcguffie, Katherine M. Dolan, Timothy L. Yahr, Dara W. Frank, Timothy S. Vincent

Dartmouth Scholarship

Exoenzyme S (ExoS), an ADP-ribosylating enzyme produced by the opportunistic pathogen Pseudomonas aeruginosa, is directly translocated into eukaryotic cells by bacterial contact. Within the cell, ExoS ADP-ribosylates the cell signaling protein Ras and causes inhibition of DNA synthesis and alterations in cytoskeletal structure. To further understand the interrelationship of the different cellular effects of ExoS, functional analyses were performed on HT-29 epithelial cells after exposure to ExoS-producing P. aeruginosa 388 and the non-ExoS-producing strain 388DeltaS. Two different mechanisms of morphological alteration were identified: (i) a more-transient and less-severe cell rounding caused by the non-ExoS-producing strain 388DeltaS and (ii) a more-severe, …

Study Of The Baig Gene In Bile Acid 7Α-Dehydroxylating Bacteria, Michael David

Masters Theses & Specialist Projects

Recently, intestinal bile acid 7α-dehydroxylating bacteria have been implicated in cholesterol gallstone disease. Eubacterium sp. strain V.P.I. 12708, a bile acid 7α-dehydroxylating bacteria, contains multiple bile acid inducible (bai) genes which are located on a large bai operon. Genes of this operon encode the enzymes responsible for bile acid 7α-dehydroxylation. The baiG gene encodes a bile acid transporter in Eubacterium sp. strain V.P.I. 12708. Utilizing the polymerase chain reaction I determined the presence or absence of baiG-like genes in six bile acid 7α-dehydroxylating strains: Clostridium sp. Strain TN-271, Eubacterium sp. strain 1-10, Clostridium bifermentans strain 1-55, Clostridium sordellii strain Y67, …

Local And Global Stereopsis In The Horse., B Timney, K Keil

Brain and Mind Institute Researchers' Publications

Although horses have laterally-placed eyes, there is substantial binocular overlap, allowing for the possibility that these animals have stereopsis. In the first experiment of the present study we measured local stereopsis by obtaining monocular and binocular depth thresholds for renal depth stimuli. On all measures, the horses' binocular performance was superior to their monocular. When depth thresholds were obtained, binocular thresholds were several times superior to those obtained monocularly, suggesting that the animals could use stereoscopic information when it was available. The binocular thresholds averaged about 15 min arc. In the second experiment we obtained evidence for the presence of …

Attachment Ligands Of Viable Toxoplasma Gondii Induce Soluble Immunosuppressive Factors In Human Monocytes, Jacqueline Y. Channon, Edward I. Suh, Rosanne M. Seguin, Lloyd H. Kasper

Dartmouth Scholarship

Previous studies have demonstrated that surface antigen proteins, in particular SAG-1, of Toxoplasma gondii are important to this parasite as attachment ligands for the host cell. An in vitro assay was developed to test whether these ligands and other secretory proteins are involved in the immune response of human cells to toxoplasma. Human monocytes were infected with tachyzoites in the presence of antiparasite antibodies, and their effect on mitogen-induced lymphoproliferation was examined. The presence of antibody to either parasite-excreted proteins (MIC-1 and MIC-2) or surface proteins (SAG-1 and SAG-2) during infection neutralized the marked decrease seen in mitogen-induced lymphoproliferation in …

Signal Transducer And Activator Of Transcription (Stat)5 Activation By Bcr/Abl Is Dependent On Intact Src Homology (Sh)3 And Sh2 Domains Of Bcr/Abl And Is Required For Leukemogenesis., M Nieborowska-Skorska, M A Wasik, A Slupianek, P Salomoni, T Kitamura, B Calabretta, T Skorski

Department of Microbiology and Immunology Faculty Papers

Signal transducer and activator of transcription (STAT)5 is constitutively activated in BCR/ ABL-expressing cells, but the mechanisms and functional consequences of such activation are unknown. We show here that BCR/ABL induces phosphorylation and activation of STAT5 by a mechanism that requires the BCR/ABL Src homology (SH)2 domain and the proline-rich binding site of the SH3 domain. Upon expression in 32Dcl3 growth factor-dependent myeloid precursor cells, STAT5 activation-deficient BCR/ABL SH3+SH2 domain mutants functioned as tyrosine kinase and activated Ras, but failed to protect from apoptosis induced by withdrawal of interleukin 3 and/or serum and did not induce leukemia in severe combined …

Perceptual-Mnemonic Functions Of The Perirhinal Cortex., Murray, Bussey

Brain and Mind Institute Researchers' Publications

It is widely acknowledged that the perirhinal cortex, located in the ventromedial aspect of the temporal lobe, is essential for certain types of memory in macaque monkeys. For example, removal of the perirhinal cortex yields severe impairments on tests of stimulus recognition and stimulus-stimulus association. There is considerable disagreement, however, about the most accurate way to characterize the function of the perirhinal cortex; some views emphasize a role in perception whereas others posit a role exclusively in declarative memory. In this article, we review recent findings from anatomical, physiological and ablation studies in monkeys, and discuss related findings obtained in …

Role Of Gamma Interferon In Cellular Immune Response Against Murine Encephalitozoon Cuniculi Infection, Imtiaz A. Khan, Magali Moretto

Dartmouth Scholarship

Microsporidia are obligate intracellular protozoan parasites that cause a wide variety of opportunistic infection in patients with AIDS. Because it is able to grow in vitro, Encephalitozoon cuniculi is currently the best-studied microsporidian. T cells mediate protective immunity against this parasite. Splenocytes obtained from infected mice proliferate in vitro in response to irradiated parasites. A transient state of hyporesponsiveness to parasite antigen and mitogen was observed at day 17 postinfection. This downregulatory response could be partially reversed by addition of nitric oxide (NO) antagonist to the culture. Mice infected withE. cuniculi secrete significant levels of gamma interferon (IFN-γ). Treatment …

Purification Of 10-5a9 Antigen In Alzheimer's Disease, Gary Isaacs

Senior Honors Theses

Alzheimer's Disease (AD) is a neurodegenerative disorder that results in memory loss and reduced cognitive function. Characteristic lesions include senile plaques and neurofibrillary tangles. Evidence for a previously unknown component, cockroach 10-5A9 antigen, within these lesions has recently been discovered. It is the purpose of this study to purify to 10-5A9 antigen for further analysis. Immunohistochemistry was used to determine the antigen's presence in AD lesions and the Lewy bodies of Parkinson's disease. Although SDS-PAGE/Western blotting and immunoprecipitation techniques proved ineffective, the former indicated antigen presence in the particulate matter of AD brain homogenates. Negative results from ammonium sulfate experiments …

Interpreting Patterns Of Gene Expression With Self-Organizing Maps: Methods And Application To Hematopoietic Differentiation, Pablo Tamayo, Donna Slonim, Jill Mesirov, Qing Zhu, Sutisak Kitareewan, Ethan Dmitrovsky

Dartmouth Scholarship

Array technologies have made it straightforward to monitor simultaneously the expression pattern of thousands of genes. The challenge now is to interpret such massive data sets. The first step is to extract the fundamental patterns of gene expression inherent in the data. This paper describes the application of self-organizing maps, a type of mathematical cluster analysis that is particularly well suited for recognizing and classifying features in complex, multidimensional data. The method has been implemented in a publicly available computer package, GENECLUSTER, that performs the analytical calculations and provides easy data visualization. To illustrate the value of such analysis, the …

Comparative Resource Use By Juvenile Parrotfishes In The Florida Keys, Karen L. Overholtzer, Philip J. Motta

Integrative Biology Faculty and Staff Publications

Many parrotfishes (Scaridae) co-occur in mixed-species aggregations as juveniles, but diverge in resource use and social structure as adults. Focal observations of 3 juvenile parrotfishes (Scarus coeruleus, Sparisoma aurofrenatum, Sparisoma viride) were conducted on inshore patch reefs in the Florida Keys to examine feeding rates, food type, habitat use, and aggressive interactions. All species overlapped extensively in their use of space and food. Home ranges physically overlapped, and the proportion of microhabitats present within home ranges was similar for all species. Home range size increased with body size for S. coeruleus and S. aurofrenatum. Diets of all …

Technique For Specifying The Fatty Acid At The Sn2 Position Of Acylglycerol Lipids, Robert C. Dickson, Robert L. Lester, M. Marek Nagiec

Molecular and Cellular Biochemistry Faculty Patents

A method for specifying a fatty acid at the sn2 position of acylglycerol lipids including (a) transfecting a vector including the SLC1 gene or a variant thereof into embryonic biological material, and (b) allowing the SLC1 gene to specify the type of fatty acid at the sn2 position of acylglycerol lipids. Also provided for is an isolated SLC1 gene and a probe for its detection.

Nucleotide Sequences For Detection Of Serpulina Hyodysenteriae, Gerald E. Duhamel, Robert Elder

School of Veterinary and Biomedical Sciences: Faculty Publications

The invention provides a method for detecting the presence of Serpulina hyodysenteriae in a biological Sample, an oligonucleotide primer and an S. hyodysenteriae-specific oligonucleotide probe useful in that method, and an article of manufacture that contains the primers and/or probe. Also provided are an about 2.3-kb DNA fragment derived from genomic DNA of S. hyodysenteriae and encoding for an about 56 kDa polypeptide, a recombinant expression vector containing the DNA fragment, the 56 kDa polypeptide and a monoclonal antibody reactive with the peptide, and a method of assaying for antibodies reactive with the 56 kDa peptide.

Genetic And Transcriptional Analyses Of The Vibrio Cholerae Mannose-Sensitive Hemagglutinin Type 4 Pilus Gene Locus, Jane W. Marsh, Ronald K. Taylor

Dartmouth Scholarship

The mannose-sensitive hemagglutinin (MSHA) of the Vibrio cholerae O1 El Tor biotype is a member of the family of type 4 pili. Type 4 pili are found on the surface of a variety of gram-negative bacteria and have demonstrated importance as host colonization factors, bacteriophage receptors, and mediators of DNA transfer. The gene locus required for the assembly and secretion of the MSHA pilus has been localized to a 16.7-kb region of the V. cholerae chromosome. Sixteen genes required for hemagglutination, including five that encode prepilin or prepilin-like proteins, have been identified. Examination of MSHA-specific cDNAs has localized two promoters …

Fas-Fasl Interaction Involved In Pathogenesis Of Ocular Toxoplasmosis In Mice, Mark S. Hu, Joseph D. Schwartzman, Grant R. Yeaman, Jane Collins, Rosanne Seguin, Imtiaz A. Khan, Lloyd H. Kasper

Dartmouth Scholarship

Ocular toxoplasmosis is a potentially blinding intraocular inflammation. The intent of this study was to investigate the role of Fas-FasL interaction in a murine model of acquired ocular toxoplasmosis induced by intracameral inoculation of Toxoplasma gondii. Intraocular inflammation, Fas and FasL expression on lymphocytes and on ocular tissues, the occurrence of apoptosis, and the frequency of CD8⁺ and CD4⁺ T cells in the infected eyes were analyzed in C57BL/6 (B6) mice. Susceptibility to parasite-induced intraocular inflammation was observed in Fas-deficient (B6-lpr) and FasL-deficient (B6-gld) mice. Inoculation of 5,000 T. gondii tachyzoites induced significant …

Antiretroviral Cytolytic T-Lymphocyte Nonresponsiveness: Fasl/Fas-Mediated Inhibition Of Cd4+ And Cd8+ Antiviral T Cells By Viral Antigen-Positive Veto Cells, Robert F. Rich, William R. Green

Dartmouth Scholarship

C57BL/6 (H-2^b ) mice generate type-specific cytolytic T-lymphocyte (CTL) responses to an immunodominant K^b-restricted epitope, KSPWFTTL located in the membrane-spanning domain of p15TM of AKR/Gross murine leukemia viruses (MuLV). AKR.H-2^b congenic mice, although carrying the responder H-2^b major histocompatibility complex (MHC) haplotype, are low responders or nonresponders for AKR/Gross MuLV-specific CTL, apparently due to the presence of inhibitory AKR.H-2^b cells. Despite their expression of viral antigens and K^b, untreated viable AKR.H-2^b spleen cells cause dramatic inhibition of the C57BL/6 (B6) antiviral CTL response to in vitro stimulation with AKR/Gross MuLV-induced …

Transgenic Mice Which Overexpress Neurotrophin-3 (Nt-3) And Method Of Use, Kathryn M. Albers, Brian M. Davis

Neuroscience Faculty Patents

Transgenic mice express increased levels of neurotrophin-3 (NT-3) in epithelium when their ancestors are microinjected with the NT-3 gene. The NT-3 growth factor expressing transgenic mice are useful in the study of neurodegenerative disorders of the brain such as Parkinson's syndrome and Alzheimer's disease, of the spinal cord motor neurons such as amyotrophic lateral sclerosis, and for testing drug candidates for the treatment of these diseases.

Modulation Of The Bursting Properties Of Single Mouse Pancreatic Β-Cells By Artificial Conductances, T.A. Kinard, G. De Vries, A. Sherman, L. S. Satin

Pharmacology and Toxicology Publications

Abstract

Glucose triggers bursting activity in pancreatic islets, which mediates the Ca²⁺ uptake that triggers insulin secretion. Aside from the channel mechanism responsible for bursting, which remains unsettled, it is not clear whether bursting is an endogenous property of individual β-cells or requires an electrically coupled islet. While many workers report stochastic firing or quasibursting in single cells, a few reports describe single-cell bursts much longer (minutes) than those of islets (15–60 s). We studied the behavior of single cells systematically to help resolve this issue. Perforated patch recordings were made from single mouseβ-cells or hamster …

The Cardiovascular And Metabolic Adaptations To Iso-Caloric Moderate Intensity And High Intensity Exercise, Summerson Desmond

Theses, Dissertations and Capstones

Cardiovascular disease is the leading cause of death in the industrialized nations, and accounts for 1 million deaths in the United States each year (McArdle, Katch & Katch, 1991). One of the major risk factors for cardiovascular disease is physical inactivity, which is a behavioral modified risk factor. Physical inactivity plagues 59% of the people in the United States (ACSM Resource Manual, 1998). Physical inactivity often leads to obesity, diabetes, hypertension and hypercholemia, and places sedentary individuals at more risk for cardiovascular disease (CVD), or coronary heart disease (CHD). The question which remains unclear is the quantity and quality of …

Genetic Monitoring In The Workplace: A Tool Not A Solution, Lillian Trettin, Catherine Musham, Richard Jablonski

RISK: Health, Safety & Environment (1990-2002)

The authors differentiate between genetic monitoring and screening, and discuss the potential risks and benefits of predictive testing technologies.

Quantitative Analysis Of Changes In Cell Volume And Intracellular Ph Induced By Ammonia And Ammonium In Neuroblastoma Cells Studied With Fluorescent Probes, Vania D. Rosas, G. Boyarsky, S. Marquez, Francisco J. Alvarez-Leefmans

Pharmacology and Toxicology Faculty Publications

No abstract provided.

A Critical Site In The Core Of The Ccr5 Chemokine Receptor Required For Binding And Infectivity Of Human Immunodeficiency Virus Type 1, Salvatore J. Siciliano, Shawn E. Kuhmann, Youmin Weng, Navid Madani, Martin S. Springer, Janet E. Lineberger, Renee Danzeisen, Michael D. Miller, Michael Kavanaugh, Julie A. Demartino, David Kabat

Biomedical and Pharmaceutical Sciences Faculty Publications

Like the CCR5 chemokine receptors of humans and rhesus macaques, the very homologous (∼98–99% identical) CCR5 of African green monkeys (AGMs) avidly binds β-chemokines and functions as a coreceptor for simian immunodeficiency viruses. However, AGM CCR5 is a weak coreceptor for tested macrophage-tropic (R5) isolates of human immunodeficiency virus type 1 (HIV-1). Correspondingly, gp120 envelope glycoproteins derived from R5 isolates of HIV-1 bind poorly to AGM CCR5. We focused on a unique extracellular amino acid substitution at the juncture of transmembrane helix 4 (TM4) and extracellular loop 2 (ECL2) (Arg for Gly at amino acid 163 (G163R)) as the likely …

Health Professions Division Catalog Academic Year 1999-2000, Nova Southeastern University

Health Professions Divisions Course Catalogs and Course Descriptions

No abstract provided.