Digital Commons Network^™

A Role For Cetp Taqib Polymorphism In Determining Susceptibility To Atrial Fibrillation: A Nested Case Control Study, Folkert W. Asselbergs, Jason H. Moore, Maarten P. Van Den Berg, Eric B. Rimm

Dartmouth Scholarship

Studies investigating the genetic and environmental characteristics of atrial fibrillation (AF) may provide new insights in the complex development of AF. We aimed to investigate the association between several environmental factors and loci of candidate genes, which might be related to the presence of AF. A nested case-control study within the PREVEND cohort was conducted. Standard 12 lead electrocardiograms were recorded and AF was defined according to Minnesota codes. For every case, an age and gender matched control was selected from the same population (n = 194). In addition to logistic regression analyses, the multifactor-dimensionality reduction (MDR) method and interaction …

Spontaneous Intracranial Arterial Dissection In The Young: Diagnosis By Ct Angiography, William C. Robertson, Curtis A. Given

Neurology Faculty Publications

BACKGROUND: Spontaneous carotid artery dissections have been rarely reported in children. Diagnosis has traditionally been confirmed by catheter arteriography. More recently diagnosis has been made by magnetic resonance imaging and magnetic resonance angiography; however the sensitivity of these techniques has yet to be determined. The authors are unaware of reports of carotid dissection confirmed by dynamic computed tomography (computerized tomographic arteriography) in the young.

CASE PRESENTATION: We recently evaluated a fourteen year-old male following the development of transient neurologic symptoms. There was no antecedent illness or trauma. Dynamic computed tomography revealed an intracranial dissection involving the supraclinoid segment of the …

Holistic Health: Does It Really Include Mental Health?, Kimberly K. Mcclanahan, Marlene B. Huff, Hatim A. Omar

Pediatrics Faculty Publications

Holistic health, incorporating mind and body as equally important and unified components of health, is a concept utilized in some health care arenas in the United States (U.S.) over the past 30 years. However, in the U.S., mental health is not seen as conceptually integral to physical health and, thus, holistic health cannot be realized until the historical concept of mind-body dualism, continuing stigma regarding mental illness, lack of mental health parity in insurance, and inaccurate public perceptions regarding mental illness are adequately addressed and resolved. Until then, mental and physical health will continue to be viewed as disparate entities …

Clinical Holistic Medicine: Holistic Sexology And Acupressure Through The Vagina (Hippocratic Pelvic Massage), Søren Ventegodt, Birgitte Clausen, Hatim A. Omar, Joav Merrick

Pediatrics Faculty Publications

Many gynecological and sexological problems (like urine incontinence, chronic pelvic pains, vulvodynia, and lack of lust, excitement, and orgasm) are resistant to standard medical treatment. In our work at the Research Clinic for Holistic Medicine in Copenhagen, we have found that vaginal acupressure, or Hippocratic pelvic massage, can help some of these problems. Technically, it is a very simple procedure as it corresponds to the explorative phase of the standard pelvic examination, supplemented with the patient's report on the feelings it provokes and the processing and integration of these feelings. Sometimes it can be very difficult to control the emotions …

Abnormal Expression Of Rest/Nrsf And Myc In Neural Stem/Progenitor Cells Causes Cerebellar Tumors By Blocking Neuronal Differentiation, Xiaohua Su, Vidya Gopalakrishnan, Duncan Stearns, Kenneth Aldape, Fredrick F Lang, Gregory Fuller, Evan Snyder, Charles G Eberhart, Sadhan Majumder

Faculty, Staff and Student Publications

Medulloblastoma, one of the most malignant brain tumors in children, is thought to arise from undifferentiated neural stem/progenitor cells (NSCs) present in the external granule layer of the cerebellum. However, the mechanism of tumorigenesis remains unknown for the majority of medulloblastomas. In this study, we found that many human medulloblastomas express significantly elevated levels of both myc oncogenes, regulators of neural progenitor proliferation, and REST/NRSF, a transcriptional repressor of neuronal differentiation genes. Previous studies have shown that neither c-Myc nor REST/NRSF alone could cause tumor formation. To determine whether c-Myc and REST/NRSF act together to cause medulloblastomas, we used a …

Length-Dependent Degradation Of Single-Stranded 3' Ends By The Werner Syndrome Protein (Wrn): Implications For Spatial Orientation And Coordinated 3' To 5' Movement Of Its Atpase/Helicase And Exonuclease Domains, Amrita Machwe, Liren Xiao, David K. Orren

Toxicology and Cancer Biology Faculty Publications

BACKGROUND: The cancer-prone and accelerated aging disease Werner syndrome is caused by loss of function of the WRN gene product that possesses ATPase, 3' to 5' helicase and 3' to 5' exonuclease activities. Although WRN has been most prominently suggested to function in telomere maintenance, resolution of replication blockage and/or recombinational repair, its exact role in DNA metabolism remains unclear. WRN is the only human RecQ family member to possess both helicase and exonuclease activity, but the mechanistic relationship between these activities is unknown. In this study, model single-stranded and 3' overhang DNA substrates of varying length and structure were …

Loss Of Sparc-Mediated Vegfr-1 Suppression After Injury Reveals A Novel Antiangiogenic Activity Of Vegf-A, Miho Nozaki, Eiji Sakurai, Brian J. Raisler, Judit Z. Baffi, Jassir Witta, Yuichiro Ogura, Rolf A. Brekken, E Helene Sage, Balamurali K. Ambati, Jayakrishna Ambati

Ophthalmology and Visual Science Faculty Publications

VEGF-A promotes angiogenesis in many tissues. Here we report that choroidal neovascularization (CNV) incited by injury was increased by excess VEGF-A before injury but was suppressed by VEGF-A after injury. This unorthodox antiangiogenic effect was mediated via VEGFR-1 activation and VEGFR-2 deactivation, the latter via Src homology domain 2-containing (SH2-containing) tyrosine phosphatase-1 (SHP-1). The VEGFR-1-specific ligand placental growth factor-1 (PlGF-1), but not VEGF-E, which selectively binds VEGFR-2, mimicked these responses. Excess VEGF-A increased CNV before injury because VEGFR-1 activation was silenced by secreted protein, acidic and rich in cysteine (SPARC). The transient decline of SPARC after injury revealed a temporal …

Research With Arctic Peoples: Unique Research Opportunities In Heart, Lung, Blood And Sleep Disorders. Working Group Summary And Recommendations, Sally Smith, Peter Bjerregaard, Hing Man Chan, André Corriveau, Sven Ebbesson, Ruth Etzel, Richard Fabsitz, Hakon Hakonarson, Carl Hild, Elizabeth Nobmann, Jeff Reading, Larisa Tereshchenko, T. Kue Young, Barbara Howard

Open Access Publications

Arctic peoples are spread over eight countries and comprise 3.74 million residents, of whom 9% are indigenous. The Arctic countries include Canada, Finland, Greenland (Denmark), Iceland, Norway, Russia, Sweden and the United States. Although Arctic peoples are very diverse, there are a variety of environmental and health issues that are unique to the Arctic regions, and research exploring these issues offers significant opportunities, as well as challenges. On July 28-29, 2004, the National Heart, Lung, and Blood Institute and the Canadian Institutes of Health Research co-sponsored a working group entitled "Research with Arctic Peoples: Unique Research Opportunities in Heart, Lung, …

Gpnn: Power Studies And Applications Of A Neural Network Method For Detecting Gene-Gene Interactions In Studies Of Human Disease, Alison A. Motsinger, Stephen L. Lee, George Mellick, Marylyn D. Ritchie

Dartmouth Scholarship

The identification and characterization of genes that influence the risk of common, complex multifactorial disease primarily through interactions with other genes and environmental factors remains a statistical and computational challenge in genetic epidemiology. We have previously introduced a genetic programming optimized neural network (GPNN) as a method for optimizing the architecture of a neural network to improve the identification of gene combinations associated with disease risk. The goal of this study was to evaluate the power of GPNN for identifying high-order gene-gene interactions. We were also interested in applying GPNN to a real data analysis in Parkinson's disease.

Competition Between The Dna Unwinding And Strand Pairing Activities Of The Werner And Bloom Syndrome Proteins, Amrita Machwe, Enerlyn M. Lozada, Liren Xiao, David K. Orren

Toxicology and Cancer Biology Faculty Publications

BACKGROUND: The premature aging and cancer-prone Werner and Bloom syndromes are caused by defects in the RecQ helicase enzymes WRN and BLM, respectively. Recently, both WRN and BLM (as well as several other RecQ members) have been shown to possess a strand annealing activity in addition to the requisite DNA unwinding activity. Since an annealing function would appear to directly oppose the action of a helicase, we have examined in this study the dynamic equilibrium between unwinding and annealing mediated by either WRN or BLM.

RESULTS: Our investigation into the competition between annealing and unwinding demonstrates that, under standard reaction …

Rab-10 Is Required For Endocytic Recycling In The Caenorhabditis Elegans Intestine, Carlos Chih-Hsiung Chen, Peter J. Schweinsberg, Shilpa Vashist, Darren P. Mareiniss, Eric J. Lambie, Barth D. Grant

Dartmouth Scholarship

The endocytic pathway of eukaryotes is essential for the internalization and trafficking of macromolecules, fluid, membranes, and membrane proteins. One of the most enigmatic aspects of this process is endocytic recycling, the return of macromolecules (often receptors) and fluid from endosomes to the plasma membrane. We have previously shown that the EH-domain protein RME-1 is a critical regulator of endocytic recycling in worms and mammals. Here we identify the RAB-10 protein as a key regulator of endocytic recycling upstream of RME-1 in polarized epithelial cells of the Caenorhabditis elegans intestine. rab-10 null mutant intestinal cells accumulate abnormally abundant RAB-5-positive early …

Heparin Modulates The 99-Loop Of Factor Ixa: Effects On Reactivity With Isolated Kunitz-Type Inhibitor Domains, Pierre F. Neuenschwander, Stephen R. Williamson, Armen Nalian, Kimberly J. Baker-Deadmond

Faculty Publications

Reactivity of factor IXa with basic pancreatic trypsin inhibitor is enhanced by low molecular weight heparin (enoxaparin). Previous studies by us have suggested that this effect involves allosteric modulation of factor IXa. We examined the reactivity of factor IXa with several isolated Kunitz-type inhibitor domains: basic pancreatic trypsin inhibitor, the Kunitz inhibitor domain of protease Nexin-2, and the first two inhibitor domains of tissue factor pathway inhibitor. We find that enhancement of factor IXa reactivity by enoxaparin is greatest for basic pancreatic trypsin inhibitor (>10-fold), followed by the second tissue factor pathway inhibitor domain (1.7-fold) and the Kunitz inhibitor …

Interdependency Of Pharmacokinetic Parameters: A Chicken-And-Egg Problem? Not!, Reza Mehvar

Pharmacy Faculty Articles and Research

Pharmacokinetic (PK) software packages are widely used by scientists in different disciplines to estimate PK parameters. However, their use without a clear understanding of physiological parameters affecting the PK parameters and how different PK parameters are related to each other may result in erroneous interpretation of data. Often, mathematical relationships used for the estimation of PK parameters obscure the true physiological relationships among these parameters, prompting a discussion of which parameter came first and giving the appearance of the-chicken-and-the-egg dilemma. In this article, the author attempts to show how different PK parameters are related to physiological parameters and each other …

Laboratory Diagnosis Of Tuberculosis In Primary Care, David Brett-Major, Thomas E. Walsh

Journal Articles: Epidemiology

No abstract provided.

Intelligent Classification Of Electrocardiogram (Ecg) Signal Using Extended Kalman Filter (Ekf) Based Neuro Fuzzy System, Y.P. Meau, F. Ibrahim, S.A.L. Narainasamy, R. Omar

Research Publications (2006 to 2010)

This study presents the development of a hybrid system consisting of an ensemble of Extended Kalman Filter (EKF) based Multi Layer Perceptron Network (MLPN) and a one-pass learning Fuzzy Inference System using Look-up Table Scheme for the recognition of electrocardiogram (ECG) signals. This system can distinguish various types of abnormal ECG signals such as Ventricular Premature Cycle (VPC), T wave inversion (TINV), ST segment depression (STDP), and Supraventricular Tachycardia (SVT) from normal sinus rhythm (NSR) ECG signal. © 2006 Elsevier Ireland Ltd. All rights reserved.

The Speciation Of Metals In Mammals Influences Their Toxicokinetics And Toxicodynamics And Therefore Human Health Risk Assessment, Robert A. Yokel, Stephen M. Lasley, David C. Dorman

Pharmaceutical Sciences Faculty Publications

Chemical form (i.e., species) can influence metal toxicokinetics and toxicodynamics and should be considered to improve human health risk assessment. Factors that influence metal speciation (and examples) include: (1) carrier-mediated processes for specific metal species (arsenic, chromium, lead and manganese), (2) valence state (arsenic, chromium, manganese and mercury), (3) particle size (lead and manganese), (4) the nature of metal binding ligands (aluminum, arsenic, chromium, lead, and manganese), (5) whether the metal is an organic versus inorganic species (arsenic, lead, and mercury), and (6) biotransformation of metal species (aluminum, arsenic, chromium, lead, manganese and mercury). The influence of speciation on metal …

Spatiotemporal Dynamics Of Networks Of Excitable Nodes, Aaron J. Steele, Mark Tinsley, Kenneth Showalter

Faculty & Staff Scholarship

No abstract provided.

An Exonic Splicing Silencer Is Involved In The Regulated Splicing Of Glucose 6-Phosphate Dehydrogenase Mrna, Wioletta Szeszel-Fedorowicz, Indrani Talukdar, Brian N. Griffith, Callee M. Walsh, Lisa M. Salati

Faculty & Staff Scholarship

No abstract provided.

Cyanidin-3-Glucoside, A Natural Product Derived From Blackberry, Exhibits Chemopreventive And Chemotherapeutic Activity, Min Ding, Rentian Feng, Shiow Y. Wang, Linda Bowman, Yongju Lu, Yong Qian, Vincent Castranova, Bing-Hua Jiang, Xianglin Shi

Faculty & Staff Scholarship

Epidemiological data suggest that consumption of fruits and vegetables has been associated with a lower incidence of cancer. Cyanidin-3-glucoside (C3G), a compound found in blackberry and other food products, was shown to possess chemopreventive and chemotherapeutic activity in the present study. In cultured JB6 cells, C3G was able to scavenge ultraviolet B-induced *OH and O2-* radicals. In vivo studies indicated that C3G treatment decreased the number of non-malignant and malignant skin tumors per mouse induced by 12-O-tetradecanolyphorbol-13-acetate (TPA) in 7,12-dimethylbenz[a]anthracene-initiated mouse skin. Pretreatment of JB6 cells with C3G inhibited UVB- and TPA-induced transactivation of NF-kappaB and AP-1 and expression of …

Antisperm Immunity For Contraception, R. K. Naz

Faculty & Staff Scholarship

No abstract provided.

Never Let Me Clone? Countering An Ethical Argument Against The Reproductive Cloning Of Humans, Yvette Pearson

Philosophy Faculty Publications

In the March 2006 issue of EMBO reports, Christof Tannert, a bioethicist at the Max Delbrück Research Centre in Berlin, Germany, presented a moral argument against human reproductive cloning on the basis of Immanuel Kant’s categorical imperative (Tannert, 2006). In this article, I address some problems with Tannert’s views and show that our concerns about this prospective procedure should prompt us to scrutinize carefully the conventional procreative practices and attitudes. Indeed, if we set aside objections that are grounded in genetic determinism, many of the offensive features of human cloning are identical to problems with procreation by more conventional means, …

Mutant Neurogenin-3 In Congenital Malabsorptive Diarrhea, Jiafang Wang, Galen Cortina, S. Vincent Wu, Robert Tran, Jang-Hyeon Cho, Ming-Jer Tsai, Travis J. Bailey, Milan Jamrich, Marvin E. Ament, William R. Treem, Ivor D. Hill, Jorge H. Vargas, George Gershman, Douglas G. Farmer, Laurie Reyen, Martin G. Martín

Biology

Background: Neurogenin-3 (NEUROG3) is expressed in endocrine progenitor cells and is required for endocrine-cell development in the pancreas and intestine. The NEUROG3 gene (NEUROG3) is therefore a candidate for the cause of a newly discovered autosomal recessive disorder characterized by generalized malabsorption and a paucity of enteroendocrine cells. Methods: We screened genomic DNA from three unrelated patients with sparse enteroendocrine cells for mutations of NEUROG3. We then tested the ability of the observed mutations to alter NEUROG3 function, using in vitro and in vivo assays. Results: The patients had few intestinal enteroendocrine cells positive for chromogranin A, but they had …

Characterization Of Hard2, A Processed Hard1 Gene Duplicate, Encoding A Human Protein N-Alpha-Acetyltransferase., Thomas Arnesen, Matthew J Betts, Frédéric Pendino, David A Liberles, Dave Anderson, Jaime Caro, Xianguo Kong, Jan E Varhaug, Johan R Lillehaug

Department of Medicine Faculty Papers

BACKGROUND: Protein acetylation is increasingly recognized as an important mechanism regulating a variety of cellular functions. Several human protein acetyltransferases have been characterized, most of them catalyzing epsilon-acetylation of histones and transcription factors. We recently described the human protein acetyltransferase hARD1 (human Arrest Defective 1). hARD1 interacts with NATH (N-Acetyl Transferase Human) forming a complex expressing protein N-terminal alpha-acetylation activity. RESULTS: We here describe a human protein, hARD2, with 81 % sequence identity to hARD1. The gene encoding hARD2 most likely originates from a eutherian mammal specific retrotransposition event. hARD2 mRNA and protein are expressed in several human cell lines. …

Innate Antiviral Response Targets Hiv-1 Release By The Induction Of Ubiquitin-Like Protein Isg15, Atsushi Okumura, Gengshi Lu, Ian Pitha-Rowe, Paula M. Pitha

Dartmouth Scholarship

The goal of this study was to elucidate the molecular mechanism by which type I IFN inhibits assembly and release of HIV-1 virions. Our study revealed that the IFN-induced ubiquitin-like protein ISG15 mimics the IFN effect and inhibits release of HIV-1 virions without having any effect on the synthesis of HIV-1 proteins in the cells. ISG15 expression specifically inhibited ubiquitination of Gag and Tsg101 and disrupted the interaction of the Gag L domain with Tsg101, but conjugation of ISG15 to Gag or Tsg101 was not detected. The inhibition of Gag-Tsg101 interaction was also detected in HIV-1 infected, IFN-treated cells. Elimination …

Statins And The Vasculopathy Of Systemic Sclerosis: Potential Therapeutic Agents?, Chris T. Derk, Sergio A. Jimenez

Department of Medicine Faculty Papers

It has been postulated that endothelial cell injury is the initiating event in the pathogenesis of systemic sclerosis, causing attraction, attachment, migration and infiltration of activated T-cells and subsequent production of cytokines and growth factors. As a result of the action of these cytokines and growth factors, chemoattraction of fibroblasts into the vessel wall and transdifferentiation of resident fibroblasts and smooth muscle cells into myofibroblasts occur leading to fibrosis and exaggerated collagen deposition in the vessel wall. To date, the therapeutic options for the vasculopathy of systemic sclerosis have been limited to drugs that cause vasodilation and inhibit platelet aggregation …

Modification Of Human Immunodeficiency Virus Type 1 Reverse Transcriptase To Target Cells With Elevated Cellular Dntp Concentrations, Varuni K. Jamburuthugoda, Pauline Chugh, Baek Kim

Biology

Retroviruses and DNA viruses utilize cellular dNTPs as substrates for their DNA polymerases during viral replication in infected cells. However, because of S phase-dependent dNTP biosynthesis, the availability of cellular dNTPs significantly varies among cell types (e.g. dividing versus nondividing cells and normal versus tumor cells). Here we tested whether alterations in the dNTP utilization efficiency and dNTP binding affinity of viral DNA polymerases can switch viral infection specificity to cell types with different dNTP concentrations. We employed an HIV-1 reverse transcriptase (RT) mutant (Q151N), which is catalytically active only at high dNTP concentrations because of its reduced dNTP binding …

Identification Of The Heparin-Binding Determinants Within Fibronectin Repeat Iii1: Role In Cell Spreading And Growth, Liqiong Gui, Katherine Wojciechowski, Candace D. Gildner, Hristina Nedelkovska, Denise C. Hocking

Biology

Fibronectins are high molecular mass glycoproteins that circulate as soluble molecules in the blood, and are also found in an insoluble, multimeric form in extracellular matrices throughout the body. Soluble fibronectins are polymerized into insoluble extracellular matrix (ECM) fibrils via a cell-dependent process. Recent studies indicate that the interaction of cells with the ECM form of fibronectin promotes actin organization and cell contractility, increases cell growth and migration, and enhances the tensile strength of artificial tissue constructs; ligation of integrins alone is insufficient to trigger these responses. Evidence suggests that the effect of ECM fibronectin on cell function is mediated …

Smc3 Knockdown Triggers Genomic Instability And P53-Dependent Apoptosis In Human And Zebrafish Cells., Giancarlo Ghiselli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: The structural maintenance of chromosome 3 (SMC3) protein is a constituent of a number of nuclear multimeric protein complexes that are involved in DNA recombination and repair in addition to chromosomal segregation. Overexpression of SMC3 activates a tumorigenic cascade through which mammalian cells acquire a transformed phenotype. This has led us to examine in depth how SMC3 level affects cell growth and genomic stability. In this paper the effect of SMC3 knockdown has been investigated. RESULTS: Mammalian cells that are SMC3 deficient fail to expand in a clonal population. In order to shed light on the underlying mechanism, experiments …

Classification And Risk Stratification Of Invasive Breast Carcinomas Using A Real-Time Quantitative Rt-Pcr Assay., Laurent Perreard, Cheng Fan, John F Quackenbush, Michael Mullins, Nicholas P Gauthier, Edward Nelson, Mary Mone, Heidi Hansen, Saundra S Buys, Karen Rasmussen, Alejandra Ruiz Orrico, Donna Dreher, Rhonda Walters, Joel Parker, Zhiyuan Hu, Xiaping He, Juan P Palazzo, Olufunmilayo I Olopade, Aniko Szabo, Charles M Perou, Philip S Bernard

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

INTRODUCTION: Predicting the clinical course of breast cancer is often difficult because it is a diverse disease comprised of many biological subtypes. Gene expression profiling by microarray analysis has identified breast cancer signatures that are important for prognosis and treatment. In the current article, we use microarray analysis and a real-time quantitative reverse-transcription (qRT)-PCR assay to risk-stratify breast cancers based on biological 'intrinsic' subtypes and proliferation. METHODS: Gene sets were selected from microarray data to assess proliferation and to classify breast cancers into four different molecular subtypes, designated Luminal, Normal-like, HER2+/ER-, and Basal-like. One-hundred and twenty-three breast samples (117 invasive …

No Vaccine Against Hiv Yet--Are We Not Perfectly Equipped?, Mahender Singh

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Enormous effort has been devoted to the development of a vaccine against human immunodeficiency virus (HIV). But it is proving to be an unprecedented challenge to create an effective vaccine mainly due to the high genetic variability of the virus and the necessity of cytotoxic T lymphocytes (CTL) for containing the infection. Currently pursued vaccine strategies appear to induce CTL in nonhuman primate models but in the early clinical trials, these strategies fail to fully control the viral infection. New strategies that can cover the vast genetic diversity of HIV are needed for the development of a potent vaccine.