Medical Sciences Commons^™

Identification Of Putative Cytoskeletal Protein Homologues In The Protozoan Host Hartmannella Vermiformis As Substrates For Induced Tyrosine Phosphatase Activity Upon Attachment To The Legionnaires' Disease Bacterium, Legionella Pneumophila, Chandrasekar Venkataraman, Lian-Yang Gao, Subbarao Bondada, Yousef Abu Kwaik

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The Legionnaires' disease bacterium, Legionella pneumophila, is a facultative intracellular pathogen that invades and replicates within two evolutionarily distant hosts, free living protozoa and mammalian cells. Invasion and intracellular replication within protozoa are thought to be major factors in the transmission of Legionnaires' disease. We have recently reported the identification of a galactose/N-acetyl-d-galactosamine (Gal/GalNAc) lectin in the protozoan host Hartmannella vermiformis as a receptor for attachment and invasion by L. pneumophila (Venkataraman, C., B.J. Haack, S. Bondada, and Y.A. Kwaik. 1997. J. Exp. Med. 186:537–547). In this report, we extended our studies to the …

Identifying Global Anatomical Differences: Deformation-Based Morphometry, J Ashburner, C Hutton, R Frackowiak, Ingrid Johnsrude, C Price, K Friston

Brain and Mind Institute Researchers' Publications

The aim of this paper is to illustrate a method for identifying macroscopic anatomical differences among the brains of different populations of subjects. The method involves spatially normalizing the structural MR images of a number of subjects so that they all conform to the same stereotactic space. Multivariate statistics are then applied to the parameters describing the estimated nonlinear deformations that ensue. To illustrate the method, we compared the gross morphometry of male and female subjects. We also assessed brain asymmetry, the effect of handedness, and interactions among these effects.

Right Medial Temporal-Lobe Contribution To Object-Location Memory, B Milner, Ingrid Johnsrude, J Crane

Brain and Mind Institute Researchers' Publications

An important aspect of normal human memory, and one humans share with many other species, is the ability to remember the location of objects in their environment. There is by now strong evidence from the study of epileptic patients undergoing brain surgery that right temporal-lobe lesions that encroach extensively upon the hippocampal and parahippocampal gyrus impair the delayed, but not the immediate, recall of the location of objects within a random array. These findings have now been extended to a multiple-trial, spatial-array learning task; by including not only patients tested after unilateral anterior temporal lobectomy but also those with a …

Stent Placement Compared With Balloon Angioplasty For Obstructed Coronary Bypass Grafts. Saphenous Vein De Novo Trial Investigators., M P Savage, J S Douglas, D L Fischman, C J Pepine, S B King, J A Werner, S R Bailey, P A Overlie, S H Fenton, J A Brinker, M B Leon, S Goldberg

Department of Medicine Faculty Papers

BACKGROUND: Treatment of stenosis in saphenous-vein grafts after coronary-artery bypass surgery is a difficult challenge. The purpose of this study was to compare the effects of stent placement with those of balloon angioplasty on clinical and angiographic outcomes in patients with obstructive disease of saphenous-vein grafts.

METHODS: A total of 220 patients with new lesions in aortocoronary-venous bypass grafts were randomly assigned to placement of Palmaz-Schatz stents or standard balloon angioplasty. Coronary angiography was performed during the index procedure and six months later.

RESULTS: As compared with the patients assigned to angioplasty, those assigned to stenting had a higher rate …

Opposing Motor Activities Are Required For The Organization Of The Mammalian Mitotic Spindle Pole, Tirso Gaglio, Alejandro Saredi, James B. Bingham, M Josh Hasbani, Steven R. Grill, Trina A. Schroer, Duane A. Compton

Dartmouth Scholarship

We use both in vitro and in vivo approaches to examine the roles of Eg5 (kinesin-related protein), cytoplasmic dynein, and dynactin in the organization of the microtubules and the localization of NuMA (Nu-clear protein that associates with the Mitotic Apparatus) at the polar ends of the mammalian mitotic spindle. Perturbation of the function of Eg5 through either immunodepletion from a cell free system for assembly of mitotic asters or antibody microinjection into cultured cells leads to organized astral microtubule arrays with expanded polar regions in which the minus ends of the microtubules emanate from a ring-like structure that contains NuMA. …

A Tandem Duplication Within The Fibrillin 1 Gene Is Associated With The Mouse Tight Skin Mutation., Linda D. Siracusa, Rodney Mcgrath, Qing Ma, John J. Moskow, Jayanthi Manne, Paul J. Christner, Arthur M. Buchberg, Sergio A. Jimenez

Department of Medicine Faculty Papers

Mice carrying the Tight skin (Tsk) mutation have thickened skin and visceral fibrosis resulting from an accumulation of extracellular matrix molecules. These and other connective tissue abnormalities have made Tskl + mice models for scleroderma, hereditary emphysema, and myocardial hypertrophy. Previously we localized Tsk to mouse chromosome 2 in a region syntenic with human chromosome 15. The microfibrillar glycoprotein gene, fibrillin 1 (FBN1), on human chromosome 15q, provided a candidate for the Tsk mutation. We now demonstrate that the Tsk chromosome harbors a 30- to 40-kb genomic duplication within the Fbn1 gene that results in a larger than normal in-frame …

Disruption Of The Cbfa2 Gene Causes Necrosis And Hemorrhaging In The Central Nervous System And Blocks Definitive Hematopoiesis., Qing Wang, Terryl Stacy, Michael M Binder, Miguel Marin-Padilla, Arlene H. Sharpe, Nancy A. Speck

Dartmouth Scholarship

The CBFA2 (AML1) gene encodes a DNA-binding subunit of the heterodimeric core-binding factor. The CBFA2 gene is disrupted by the (8;21), (3;21), and (12;21) chromosomal translocations associated with leukemias and myelodysplasias in humans. Mice lacking a CBF alpha 2 protein capable of binding DNA die between embryonic days 11.5 and 12.5 due to hemorrhaging in the central nervous system (CNS), at the nerve/CNS interfaces of cranial and spinal nerves, and in somitic/intersomitic regions along the presumptive spinal cord. Hemorrhaging is preceded by symmetric, bilateral necrosis in these regions. Definitive erythropoiesis and myelopoiesis do not occur in Cbfa2-deficient embryos, and disruption …

Cd40-Cd40 Ligand Interactions In Experimental Allergic Encephalomyelitis And Multiple Sclerosis., Koen Gerritse, Jon D. Laman, Randolph J. Noelle, Alejandro Aruffo

Dartmouth Scholarship

We investigated the role of CD40-CD40 ligand (CD40L) interactions in multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). Activated helper T cells expressing CD40L (gp39) surface protein were found in MS patient brain sections, but not in brain tissue sections of normal controls or patients with other neurological disease. CD40L-positive cells were co-localized with CD40-bearing cells in active lesions (perivascular infiltrates). Most of these CD40-bearing cells proved to be of the monocytic lineage (macrophages or microglial cells), and relatively few were B cells. To functionally evaluate CD40-CD40L interactions, EAE was elicited in mice by means of proteolipid-peptide immunization. Treatment with …

Anti-Human Immunodeficiency Virus (Hiv) Activities Of Halogenated Gomisin J Derivatives, New Nonnucleoside Inhibitors Of Hiv Type 1 Reverse Transcriptase, Toshiaki Fujihashi, Hiroto Hara, Toshiya Sakata, Kazuya Mori, Hirotaka Higuchi, Akio Tanaka, Hideko Kaji, Akira Kaji

Department of Biochemistry and Molecular Biology Faculty Papers

Halogenated gomisin J (a derivative of lignan compound), represented by the bromine derivative 1506 [(6R, 7S, S-biar)-4,9-dibromo-3,10-dihydroxy-1,2,11,12-tetramethoxy-6, 7-dimethyl-5,6,7,8- tetrahydrodibenzo[a,c]cyclo-octene], was found to be a potent inhibitor of the cytopathic effects of human immunodeficiency virus type 1 (HIV-1) on MT-4 human T cells (50% effective dose, 0.1 to 0.5 microM). Gomisin J derivatives were active in preventing p24 production from acutely HIV-1-infected H9 cells. The selective indices (toxic dose/effective dose) of these compounds were as high as > 300 in some systems. 1506 was active against 3'-azido-3'-deoxythymidine-resistant HIV-1 and acted synergistically with AZT and 2',3'-ddC. 1506 inhibited HIV-1 reverse transcriptase (RT) in …

A Randomized Comparison Of Coronary-Stent Placement And Balloon Angioplasty In The Treatment Of Coronary Artery Disease. Stent Restenosis Study Investigators., David L. Fischman, Martin B. Leon, Donald S. Baim, Richard A. Schatz, Michael P. Savage, Ian Penn, Katherine Detre, Lisa Veltri, Donald Ricci, Masakiyo Nobuyoshi, Michael Cleman, Richard Heuser, David Almond, Paul S. Teirstein, R. David Fish, Antonio Colombo, Jeffrey Brinker, Jeffrey Moses, Alex Shaknovich, John Hirshfeld, Stephen Bailey, Stephen Ellis, Randal Rake, Sheldon Goldberg

Department of Medicine Faculty Papers

BACKGROUND: Coronary-stent placement is a new technique in which a balloon-expandable, stainless-steel, slotted tube is implanted at the site of a coronary stenosis. The purpose of this study was to compare the effects of stent placement and standard balloon angioplasty on angiographically detected restenosis and clinical outcomes.

METHODS: We randomly assigned 410 patients with symptomatic coronary disease to elective placement of a Palmaz-Schatz stent or to standard balloon angioplasty. Coronary angiography was performed at base line, immediately after the procedure, and six months later.

RESULTS: The patients who underwent stenting had a higher rate of procedural success than those who …

Comparison Of Cytotoxic Properties Of Neonatal And Adult Neutrophils And Monocytes And Enhancement By Cytokines., E . R. Stiehm, R. L. Roberts, B. J. Ank, S. Plaeger-Marshall, N. Salman, L. Shen, M. W. Fanger

Dartmouth Scholarship

We studied cytotoxic capabilities of newborn polymorphonuclear leukocytes (PMNs) and monocytes and their enhancement by cytokines and antibodies. Umbilical cord PMNs were assessed for their ability to kill various target cells spontaneously, after activation with phorbol myristate acetate, in the presence of antiserum (antibody-dependent cellular cytotoxicity), and in the presence of dually specific antibody (heteroantibody-mediated cytotoxicity). Target cells included the K562 cell line (natural killer cell target), chicken erythrocytes (CRBCs), and herpes simplex virus-infected CEM cell lines. Newborn PMNs were equivalent to adult PMNs in their cytotoxic capacity in several cytotoxicity assays. Neither adult nor newborn PMNs lyse tumor cell …

Estimation Of The Incidence Of A Rare Genetic Disease Through A Two-Tier Mutation Survey, R Chakraborty, M R Srinivasan, S Raskin

Faculty, Staff and Student Publications

Recent attempts to detect mutations involving single base changes or small deletions that are specific to genetic diseases provide an opportunity to develop a two-tier mutation-screening program through which incidence of rare genetic disorders and gene carriers may be precisely estimated. A two-tier survey consists of mutation screening in a sample of patients with specific genetic disorders and in a second sample of newborns from the same population in which mutation frequency is evaluated. We provide the statistical basis for evaluating the incidence of affected and gene carriers in such two-tier mutation-screening surveys, from which the precision of the estimates …

Can An Anesthesia Machine Flush Valve Provide For Effective Jet Ventilation?, S D Gaughan, J L Benumof, G T Ozaki

Faculty, Staff and Student Publications

Transtracheal jet ventilation (TTJV) using a percutaneously inserted intravenous (IV) catheter for the patient who cannot be ventilated or tracheally intubated or, using a jet stylet for changing endotracheal tubes (ETT) in patients for whom subsequent ventilation and/or tracheal reintubation may be difficult, are extremely valuable therapeutic options. The jet ventilation system must have a sufficiently high pressure-oxygen source to drive oxygen through noncompliant tubing and through relatively small IV catheters and/or jet stylets in order to achieve adequate ventilation and oxygenation. There is no evidence that using the common gas outlet of an anesthesia machine by activating the flush …

Indistinguishable Nuclear Factor Binding To Functional Core Sites Of The T-Cell Receptor Delta And Murine Leukemia Virus Enhancers., Juan M. Redondo, Jeffrey L. Pfohl, Cristina Hernandez-Munain, Shuwen Wang, Nancy A. Speck, Michael S. Krangel

Dartmouth Scholarship

We have previously shown that the delta E3 site is an essential element for transcriptional activation by the human T-cell receptor (TCR) delta enhancer and identified two factors, NF-delta E3A and NF-delta E3C, that bound to overlapping core (TGTGGTTT) and E-box motifs within delta E3. In this study, we show that protein binding to the core motif is necessary but not sufficient for transcriptional activation by the delta E3 element. In contrast, protein binding to the E-box motif does not contribute significantly to enhancer activity. A similar core motif present within the enhancers of T-cell-tropic murine retroviruses has been shown …

A Phorbol Ester Response Element Within The Human T-Cell Receptor Beta-Chain Enhancer., Haydn M. Prosser, David Wotton, Anne Gegonne, Jacques Ghysdael, Shuwen Wang, Nancy A. Speck, Michael J. Owen

Dartmouth Scholarship

The activity of the T-cell receptor beta-chain gene enhancer is increased by activators of the protein kinase C pathway during T-cell activation. Analysis of mutant enhancer constructs identified two elements, beta E2 and beta E3, conferring phorbol ester inducibility. Multimerized beta E2 acted in isolation as a phorbol ester-responsive element. Both beta E2 and beta E3, which contain a consensus Ets-binding site, were shown to bind directly to the product of the c-ets-1 protooncogene. Both regions also bound a second factor, core-binding factor. Mutation of the beta E2 Ets site abolished the inducibility of the beta E2 multimer. beta E2 …

Statistical Interpretation Of Dna Typing Data, R Chakraborty

Faculty, Staff and Student Publications

No abstract provided.

Inclusion Of Data On Relatives For Estimation Of Allele Frequencies, R Chakraborty

Faculty, Staff and Student Publications

No abstract provided.

Interleukin-2-Triggered Raf-1 Expression, Phosphorylation, And Associated Kinase Activity Increase Through G1 And S In Cd3-Stimulated Primary Human T Cells., Antanina Zmuidzinas, Harvey J. Mamon, Thomas M. Roberts, Kendall A. Smith

Dartmouth Scholarship

To gain further insight into the role of Raf-1 in normal cell growth, c-raf-1 mRNA expression, Raf-1 protein production, and Raf-1-associated kinase activity in normal human T cells were analyzed. In contrast to the constitutive expression of Raf-1 in continuously proliferating cell lines, c-raf-1 mRNA and Raf-1 protein levels were barely detectable in freshly isolated G0 T lymphocytes. Previous work with fibroblasts has suggested that Raf-1 plays a signaling role in the G0-G1 phase transition. In T cells, triggering via the T-cell antigen receptor (TCR)-CD3 complex (TCR/CD3) resulted in an approximately fourfold increase in c-raf-1 mRNA. In addition, the promotion …

Fibril In Senile Systemic Amyloidosis Is Derived From Normal Transthyretin., Per Westermark, Knut Sletten, Bjorn Johansson, Gibbons G. Cornwell

Dartmouth Scholarship

The amyloid fibril in senile systemic amyloidosis (SSA), like that of familial amyloidotic polyneuropathy, is derived from transthyretin (TTR). SSA, however, is a common disease, affecting to some degree 25% of the population greater than 80 years old. In familial amyloidotic polyneuropathy, the amyloidogenesis has been considered to depend on point mutations leading to TTR variants. We show that the TTR molecule in SSA, on the other hand, has a normal primary structure. Factors other than the primary structure of TTR must therefore be important in the pathogenesis of TTR-derived amyloid.

Murine Gamma Interferon Fails To Inhibit Toxoplasma Gondii Growth In Murine Fibroblasts., Joseph D. Schwartzman, Steven L. Gonias, E R. Pfefferkorn

Dartmouth Scholarship

Although treatment of human macrophages or fibroblasts with human gamma interferon results in the inhibition of intracellular Toxoplasma gondii, murine gamma interferon stimulated only murine macrophages, not murine fibroblasts, to inhibit T. gondii. This species difference may be important in understanding the control of acute and chronic toxoplasmosis.

Maternal-Neonatal Serum Vitamin A Concentrations., Girish S. Shirali, D G. Oelberg, K P. Mehta

Manuscripts, Articles, Book Chapters and Other Papers

Prevention of neonatal vitamin A deficiency is related to the adequacy of maternal vitamin A stores. In this study we investigated maternal and cord serum vitamin A and retinol-binding protein (RBP) values in an Indian population including, for the first time, clinically vitamin A-deficient mothers. Twenty-eight maternal-neonatal pairs were selected from maternal cohorts of high socioeconomic status without clinical evidence of vitamin A deficiency (group I) and low socioeconomic status with conjunctival xerosis and Bitot's spots (group II). Maternal education, caloric and vitamin A intakes, weight, height, hemoglobin, and birth weight were significantly lower in group II. Serum vitamin A …

The Epidermal Growth Factor Receptor From Prostate Cells Is Dephosphorylated By A Prostate-Specific Phosphotyrosyl Phosphatase., Ming-Fong Lin, Gail M. Clinton

Journal Articles: Biochemistry & Molecular Biology

Human prostatic acid phosphatase (PAcP) has been found to have phosphotyrosyl-protein phosphatase activity (H. C. Li, J. Chernoff, L. B. Chen, and A. Kirschonbaun, Eur. J. Biochem. 138:45-51, 1984; M.-F. Lin and G. M. Clinton, Biochem. J. 235:351-357, 1986) and has been suggested to negatively regulate phosphotyrosine levels, at least in part, by inhibition of tyrosine protein kinase activity (M.-F. Lin and G. M. Clinton, Adv. Protein Phosphatases 4:199-228, 1987; M.-F. Lin, C. L. Lee, and G. M. Clinton, Mol. Cell. Biol. 6:4753-4757, 1986). We investigated the molecular interaction of PAcP with a specific tyrosine kinase, the epidermal growth factor …

Population Amalgamation And Genetic Variation: Observations On Artificially Agglomerated Tribal Populations Of Central And South America, R Chakraborty, P E Smouse, J V Neel

Faculty, Staff and Student Publications

The interpretation of data on genetic variation with regard to the relative roles of different evolutionary factors that produce and maintain genetic variation depends critically on our assumptions concerning effective population size and the level of migration between neighboring populations. In humans, recent population growth and movements of specific ethnic groups across wide geographic areas mean that any theory based on assumptions of constant population size and absence of substructure is generally untenable. We examine the effects of population subdivision on the pattern of protein genetic variation in a total sample drawn from an artificial agglomerate of 12 tribal populations …

Camp Antagonizes Interleukin 2-Promoted T-Cell Cycle Progression At A Discrete Point In Early G1., Kirk W. Johnson, Bruce H. Davis, Kendall A. Smith

Dartmouth Scholarship

T lymphocytes are stimulated to proliferate in an autocrine/paracrine manner by the lymphokine interleukin 2 (IL-2). In seeking further insight into the mechanisms by which IL-2 induces progression of T cells through the G1 phase of the cell cycle, studies were performed with agents that increase cellular adenosine 3',5'-cyclic monophosphate (cAMP), a well-known inhibitor of lymphocyte growth. The addition of dibutyryl-cAMP, cholera toxin, forskolin, or 3-isobutyl-1-methylxanthine to an IL-2-dependent murine T-cell line evoked a dose-related suppression of S-phase transition without affecting cellular viability. Moreover, elevation of cAMP levels led to an accumulation of uniformly small cells, suggesting an arrest in …

K+ Efflux In Nih Mouse 3t3 Cells And Transformed Derivatives: Dependence On Extracellular Ca2+ And Phorbol Esters., Martin Lubin

Dartmouth Scholarship

In culture medium deficient in Ca2+, NIH mouse 3T3 cells lose K+, gain Na+, and stop growing. A marked increase in the rate of K+ efflux accounts for this loss; Na+, K+-ATPase pump activity increases but does not fully compensate for enhanced K+ efflux. Phorbol esters and cycloheximide inhibit K+ loss in Ca2+-deficient medium. Phorbol esters inhibit K+ efflux from human fibroblasts as well, even at physiological levels of Ca2+. Two cell lines derived from NIH-3T3, one transformed by a simian virus 40 deletion mutant, the other by the polyoma virus oncogene encoding the middle-sized tumor antigen, retain K+ and …

Psammoma Bodies In Neuroendocrine Carcinoma Of The Uterine Cervix., V L. Russin, Philip T. Valente, P Hanjani

Department of Pathology & Laboratory Medicine

No abstract provided.

Developmental Expression Of Tyrosyl Kinase Activity In Human Serum., Ming-Fong Lin, Joan E. Bailey-Wilson, Robert C. Elston, Gail M. Clinton

Journal Articles: Biochemistry & Molecular Biology

Tyrosine protein kinases, in addition to their roles as viral transforming proteins and growth factor receptors, have been suggested to have specialized functions in tissue specific processes and in differentiation. High levels of soluble tyrosine kinases have been found in human serum and plasma. To determine if the level of tyrosine kinase activity is development tally expressed in human serum, we assayed sera from 214 individuals of different ages from newborns to 90 years. We found that serum tyrosine kinase levels are high in newborns and the levels closely parallel skeletal growth until late adolescence. The serum tyrosine kinase levels …

Tyrosyl Kinase Activity Is Inversely Related To Prostatic Acid Phosphatase Activity In Two Human Prostate Carcinoma Cell Lines., Ming-Fong Lin, Ching-Li Lee, Gail M. Clinton

Journal Articles: Biochemistry & Molecular Biology

Alterations in prostatic acid phosphatase (PAcP), a phosphotyrosyl phosphatase, corresponded to changes in overall tyrosyl kinase activity. PAcP added to extracts of prostate carcinoma cells with a low endogenous level of PAcP activity and elevated tyrosyl kinase activity decreased the tyrosyl kinase activity. On the other hand, when PAcP activity was decreased by the addition of androgens to cells, there was a corresponding increase in tyrosyl kinase activity.

Recognition And Characterization Of Stage-Specific Oocyst/Sporozoite Antigens Of Toxoplasma Gondii By Human Antisera., Lloyd H. Kasper, Patricia L. Ware

Dartmouth Scholarship

Human infection with Toxoplasma gondii is presumed due to the ingestion of either tissue cysts containing bradyzoites or oocyst/sporozoites that are excreted in the feces of infected cats. The incidence of human infection in the general population by either of these routes is unknown. We have previously described unique stage-specific oocyst/sporozoite antigens identified by murine hybridoma monoclonal antibodies. We obtained acute and convalescent antitoxoplasma antisera from patients in an epidemiologically well-documented outbreak of oocyst-transmitted infection associated with the ingestion of contaminated water. An enzyme-linked immunosorbent assay comparing equal numbers of tachyzoites (invasive stage) and oocyst/sporozoite (excreted stage) indicated that these …

Interleukin 2 Regulates Its Own Receptors., Kendall A. Smith, Doreen A. Cantrell

Dartmouth Scholarship

The cell surface density of high-affinity membrane receptors for the T-lymphocytotrophic hormone interleukin 2 (IL-2) determines the rate of T-cell-cycle progression. Since 10-fold greater numbers of IL-2 receptor molecules were found by using a radiolabeled monoclonal antibody reactive with IL-2 receptors (anti-Tac) compared with binding of IL-2, the functional relationship of the binding sites recognized by both of these ligands was assessed. In the presence of cycloheximide, IL-2 binding sites declined with a half-time (t1/2) of 2.6 hr, whereas the decay of anti-Tac binding sites was much slower (t 1/2 = 6.4 hr). Moreover, after limited membrane proteolysis, the half-time …