Digital Commons Network^™

Polymorphisms In Nucleotide Excision Repair Genes, Arsenic Exposure, And Non-Melanoma Skin Cancer In New Hampshire, Katie M. Applebaum, Margaret R. Karagas, David J. Hunter, Paul J. Catalano, Steven H. Byler, Steve Morris, Heather H. Nelson

Dartmouth Scholarship

Background:

Arsenic exposure may alter the efficiency of DNA repair. UV damage is specifically repaired by nucleotide excision repair (NER), and common genetic variants in NER may increase risk for non-melanoma skin cancer (NMSC).

Objective:

We tested whether polymorphisms in the NER genes XPA (A23G) and XPD (Asp312Asn and Lys751Gln) modify the association between arsenic and NMSC.

Methods:

Incident cases of basal and squamous cell carcinoma (BCC and SCC, respectively) were identified through a network of dermatologists and pathology laboratories across New Hampshire. Population-based controls were frequency matched to cases on age and sex. Arsenic exposure was assessed in toenail …

Platelet Hyperreactivity: Predictive And Intrinsic Properties., Paul F. Bray

Cardeza Foundation for Hematologic Research

Platelet thrombi are central to the development of most vascular ischemic events. There is marked interindividual variation in platelet responsiveness, with some subjects displaying platelet hyperreactivity. An increasing number of reports indicate that there are laboratory measures of platelet function that predict clinical thrombotic events. Some, but not all, measures of platelet function are reproducible. Platelet hyperreactivity can be assessed with multiple stimuli in multiple assays and is more likely to be present in women and in subjects who have elevated fibrinogen levels.

Inducible Caspase 9 Suicide Gene To Improve The Safety Of Allodepleted T Cells After Haploidentical Stem Cell Transplantation, Siok-Keen Tey, Gianpietro Dotti, Cliona M. Rooney, Helen E. Heslop, Malcolm K. Brenner

Faculty, Staff and Students Publications

Addback of donor T cells following T cell-depleted stem cell transplantation (SCT) can accelerate immune reconstitution and be effective against relapsed malignancy. After haploidentical SCT, a high risk of graft-versus-host disease (GVHD) essentially precludes this option, unless the T cells are first depleted of alloreactive precursor cells. Even then, the risks of severe GVHD remain significant. To increase the safety of the approach and thereby permit administration of larger T cell doses, we used a suicide gene, inducible caspase 9 (iCasp9), to transduce allodepleted T cells, permitting their destruction should administration have adverse effects. We made a retroviral vector encoding …

American Academy Of Allergy, Asthma & Immunology Work Group Report: Allergy Diagnosis In Clinical Practice, Dana V. Wallace, Sami L. Bahna, Stan Goldstein, Robert G. Hamilton, John R. Cohn

Department of Medicine Faculty Papers

No abstract provided.

In Search Of Polymorphic Alu Insertions With Restricted Geographic Distributions, Richard Cordaux, Deepa Srikanta, Jungnam Lee, Mark Stoneking, Mark A. Batzer

Faculty Publications

Alu elements are transposable elements that have reached over one million copies in the human genome. Some Alu elements inserted in the genome so recently that they are still polymorphic for insertion presence or absence in human populations. Recently, there has been an increasing interest in using Alu variation for studies of human population genetic structure and inference of individual geographic origin. Currently, this requires a high number of Alu loci. Here, we used a linker-mediated polymerase chain reaction method to preferentially identify low-frequency Alu elements in various human DNA samples with different geographic origins. The candidate Alu loci were …

Energizing Mirna Research: A Review Of The Role Of Mirnas In Lipid Metabolism, With A Prediction That Mir-103/107 Regulates Human Metabolic Pathways, Bernard R. Wilfred, Wang-Xia Wang, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

MicroRNAs (miRNAs) are powerful regulators of gene expression. Although first discovered in worm larvae, miRNAs play fundamental biological roles-including in humans-well beyond development. MiRNAs participate in the regulation of metabolism (including lipid metabolism) for all animal species studied. A review of the fascinating and fast-growing literature on miRNA regulation of metabolism can be parsed into three main categories: (1) adipocyte biochemistry and cell fate determination; (2) regulation of metabolic biochemistry in invertebrates; and (3) regulation of metabolic biochemistry in mammals. Most research into the 'function' of a given miRNA in metabolic pathways has concentrated on a given miRNA acting upon …

Navigating The Us Health Care System: A Video Guide For Immigrant And Diverse Populations., Alison M Bobal, Heather L Brown, Teresa L Hartman, Marty Magee, Cynthia M Schmidt

Journal Articles: Leon S. McGoogan Health Sciences Library

No abstract provided.

Epstein-Barr Virus Infection Of Langerhans Cell Precursors As A Mechanism Of Oral Epithelial Entry, Persistence, And Reactivation, Dennis M. Walling, Autumn J. Ray, Joan E. Nichols, Catherine M. Flaitz, C. Mark Nichols

Faculty, Staff and Student Publications

Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus associated with many malignant and nonmalignant human diseases. Life-long latent EBV persistence occurs in blood-borne B lymphocytes, while EBV intermittently productively replicates in mucosal epithelia. Although several models have previously been proposed, the mechanism of EBV transition between these two reservoirs of infection has not been determined. In this study, we present the first evidence demonstrating that EBV latently infects a unique subset of blood-borne mononuclear cells that are direct precursors to Langerhans cells and that EBV both latently and productively infects oral epithelium-resident cells that are likely Langerhans cells. These data …

Neural Reprogramming In Retinal Degeneration, Robert E Marc, Bryan W Jones, James R Anderson, Krista Kinard, David W Marshak, John H Wilson, Theodore Wensel, Robert J Lucas

Faculty, Staff and Student Publications

PURPOSE: Early visual defects in degenerative diseases such as retinitis pigmentosa (RP) may arise from phased remodeling of the neural retina. The authors sought to explore the functional expression of ionotropic (iGluR) and group 3, type 6 metabotropic (mGluR6) glutamate receptors in late-stage photoreceptor degeneration.

METHODS: Excitation mapping with organic cations and computational molecular phenotyping were used to determine whether retinal neurons displayed functional glutamate receptor signaling in rodent models of retinal degeneration and a sample of human RP.

RESULTS: After photoreceptor loss in rodent models of RP, bipolar cells lose mGluR6 and iGluR glutamate-activated currents, whereas amacrine and ganglion …

Meeting Report: The Role Of Environmental Lighting And Circadian Disruption In Cancer And Other Diseases, Richard G. Stevens, David E. Blask, George C. Brainard, Johnni Hansen, Steven W. Lockley, Ignacio Provencio, Mark S. Rea, Leslie Reinlib

Department of Neurology Faculty Papers

Light, including artificial light, has a range of effects on human physiology and behavior and can therefore alter human physiology when inappropriately timed. One example of potential light-induced disruption is the effect of light on circadian organization, including the production of several hormone rhythms. Changes in light-dark exposure (e.g., by nonday occupation or transmeridian travel) shift the timing of the circadian system such that internal rhythms can become desynchronized from both the external environment and internally with each other, impairing our ability to sleep and wake at the appropriate times and compromising physiologic and metabolic processes. Light can also have …

Endothelial Stomatal And Fenestral Diaphragms In Normal Vessels And Angiogenesis, R. V. Stan

Dartmouth Scholarship

Vascular endothelium lines the entire cardiovascular system where performs a series of vital functions including the control of microvascular permeability, coagulation inflammation, vascular tone as well as the formation of new vessels via vasculogenesis and angiogenesis in normal and disease states. Normal endothelium consists of heterogeneous populations of cells differentiated according to the vascular bed and segment of the vascular tree where they occur. One of the cardinal features is the expression of specific subcellular structures such as plasmalemmal vesicles or caveolae, transendothelial channels, vesiculo-vacuolar organelles, endothelial pockets and fenestrae, whose presence define several endothelial morphological types. A less explored …

Alcohol Slows Interhemispheric Transmission, Increases The Flash-Lag Effect, And Prolongs Masking: Evidence For A Slowing Of Neural Processing And Transmission., Sarah A Khan, Brian Timney

Brain and Mind Institute Researchers' Publications

While the alcohol literature is extensive, relatively little addresses the relationship between physiological effects and behavioural changes. Using the visual system as a model, we examined alcohol's influence on neural temporal processing as a potential means for alcohol's effects. We did this by using tasks that provided a measure of processing speed: Poffenberger paradigm, flash-lag, and backward masking. After moderate alcohol, participants showed longer interhemispheric transmission times, larger flash-lags, and prolonged masking. Our data are consistent with the view that alcohol slows neural processing, and provide support for a reduction in processing efficiency underlying alcohol-induced changes in temporal visual processing.

The Pharmacokinetics Of Taurolidine Metabolites In Healthy Volunteers., Li Gong, Howard E Greenberg, James L Perhach, Scott A Waldman, Walter K. Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Taurolidine is an experimental antibacterial and antiendotoxic compound whose clinical utility as an antitumor agent is being investigated in human clinical trials. Taurolidine in aqueous solution exists in equilibrium with taurultam. Taurultam is subsequently transformed to taurinamide. The pharmacokinetic profiles of these metabolites are not well established. In this study, 18 healthy volunteers were administered 5.0 g of taurolidine in 250 mL of 5% polyvinylpyrrolidone in water over 2, 1, or 0.5 hours by intravenous infusion in a parallel-group design. All subjects noted discomfort at the infusion site, although there were no serious adverse events. t(max) generally occurred at the …

Concave Pit-Containing Scaffold Surfaces Improve Stem Cell-Derived Osteoblast Performance And Lead To Significant Bone Tissue Formation., Antonio Graziano, Riccardo D'Aquino, Maria Gabriella Cusella-De Angelis, Gregorio Laino, Adriano Piattelli, Maurizio Pacifici, Alfredo De Rosa, Gianpaolo Papaccio

Department of Orthopaedic Surgery Faculty Papers

BACKGROUND: Scaffold surface features are thought to be important regulators of stem cell performance and endurance in tissue engineering applications, but details about these fundamental aspects of stem cell biology remain largely unclear.

METHODOLOGY AND FINDINGS: In the present study, smooth clinical-grade lactide-coglyolic acid 85:15 (PLGA) scaffolds were carved as membranes and treated with NMP (N-metil-pyrrolidone) to create controlled subtractive pits or microcavities. Scanning electron and confocal microscopy revealed that the NMP-treated membranes contained: (i) large microcavities of 80-120 microm in diameter and 40-100 microm in depth, which we termed primary; and (ii) smaller microcavities of 10-20 microm in diameter …

Importance Of The Ebp (Endocarditis- And Biofilm-Associated Pilus) Locus In The Pathogenesis Of Enterococcus Faecalis Ascending Urinary Tract Infection, Kavindra V Singh, Sreedhar R Nallapareddy, Barbara E Murray

Faculty, Staff and Student Publications

BACKGROUND: We recently demonstrated that the ubiquitous Enterococcus faecalis ebp (endocarditis- and biofilm-associated pilus) operon is important for biofilm formation and experimental endocarditis. Here, we assess its role in murine urinary tract infection (UTI) by use of wild-type E. faecalis OG1RF and its nonpiliated, ebpA allelic replacement mutant (TX5475).

METHODS: OG1RF and TX5475 were administered transurethrally either at an ~1 : 1 ratio (competition assay) or individually (monoinfection). Kidney pairs and urinary bladders were cultured 48 h after infection. These strains were also tested in a peritonitis model.

RESULTS: No differences were observed in the peritonitis model. In mixed UTIs, …

Acquisition Of A Natural Resistance Gene Renders A Clinical Strain Of Methicillin-Resistant Staphylococcus Aureus Resistant To The Synthetic Antibiotic Linezolid, Seok-Ming Toh, Liqun Xiong, Cesar A Arias, Maria V Villegas, Karen Lolans, John Quinn, Alexander S Mankin

Faculty, Staff and Student Publications

Linezolid, which targets the ribosome, is a new synthetic antibiotic that is used for treatment of infections caused by Gram-positive pathogens. Clinical resistance to linezolid, so far, has been developing only slowly and has involved exclusively target site mutations. We have discovered that linezolid resistance in a methicillin-resistant Staphylococcus aureus hospital strain from Colombia is determined by the presence of the cfr gene whose product, Cfr methyltransferase, modifies adenosine at position 2503 in 23S rRNA in the large ribosomal subunit. The molecular model of the linezolid-ribosome complex reveals localization of A2503 within the drug binding site. The natural function of …

The Kinesin-13 Proteins Kif2a, Kif2b, And Kif2c/Mcak Have Distinct Roles During Mitosis In Human Cells, Amity L. Manning, Neil J. Ganem, Samuel F. Bakhoum, Michael Wagenbach, Linda Wordeman, Duane A. Compton

Dartmouth Scholarship

The human genome has three unique genes coding for kinesin-13 proteins called Kif2a, Kif2b, and MCAK (Kif2c). Kif2a and MCAK have documented roles in mitosis, but the function of Kif2b has not been defined. Here, we show that Kif2b is expressed at very low levels in cultured cells and that GFP-Kif2b localizes predominately to centrosomes and midbodies, but also to spindle microtubules and transiently to kinetochores. Kif2b-deficient cells assemble monopolar or disorganized spindles. Chromosomes in Kif2b-deficient cells show typical kinetochore-microtubule attachments, but the velocity of movement is reduced ∼80% compared with control cells. Some Kif2b-deficient cells attempt anaphase, but the …

The Pseudomonas Aeruginosa Secreted Protein Pa2934 Decreases Apical Membrane Expression Of The Cystic Fibrosis Transmembrane Conductance Regulator, Daniel P. Maceachran, Siying Ye, Jennifer M. Bomberger, Deborah A. Hogan, Agnieszka Swiatecka-Urban, Bruce Stanton, George A. O'Toole

Dartmouth Scholarship

We previously reported that Pseudomonas aeruginosa PA14 secretes a protein that can reduce the apical membrane expression of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Here we report that we have used a proteomic approach to identify this secreted protein as PA2934 [corrected], and we have named the gene cif, for CFTR inhibitory factor. We demonstrate that Cif is a secreted protein and is found associated with outer membrane-derived vesicles. Expression of Cif in Escherichia coli and purification of the C-terminal six-His-tagged Cif protein showed that Cif is necessary and sufficient to mediate the reduction in apical membrane expression …

Detecting Agency From The Biological Motion Of Veridical Vs Animated Agents, Raymond A. Mar, William M. Kelley, Todd F. Heatherton, C. Neil Macrae

Dartmouth Scholarship

The ability to detect agency is fundamental for understanding the social world. Underlying this capacity are neural circuits that respond to patterns of intentional biological motion in the superior temporal sulcus and temporoparietal junction. Here we show that the brain's blood oxygenation level dependent (BOLD) response to such motion is modulated by the representation of the actor. Dynamic social interactions were portrayed by either live-action agents or computer-animated agents, enacting the exact same patterns of biological motion. Using an event-related design, we found that the BOLD response associated with the perception and interpretation of agency was greater when identical physical …

Efficacy Of The De Novo-Derived Antimicrobial Peptide Wlbu2 Against Oral Bacteria, Karen F. Novak, William J. Diamond, Sreenatha S. Kirakodu, Rebecca Peyyala, Kimberly W. Anderson, Ronald C. Montelaro, Timothy A. Mietzner

Center for Oral Health Research Faculty Publications

The efficacy of a novel synthetic antimicrobial peptide (WLBU2) was evaluated against three oral microorganisms (grown planktonically): Streptococcus gordonii, Fusobacterium nucleatum, and Porphyromonas gingivalis. WLBU2 killed all three species, with F. nucleatum being the most susceptible. WLBU2 also reduced the bacterial burden of S. gordonii and F. nucleatum biofilms.

The Extracellular Matrix And Blood Vessel Formation: Not Just A Scaffold, John M. Rhodes, Michael Simons

Dartmouth Scholarship

The extracellular matrix plays a number of important roles, among them providing structural support and information to cellular structures such as blood vessels imbedded within it. As more complex organisms have evolved, the matrix ability to direct signalling towards the vasculature and remodel in response to signalling from the vasculature has assumed progressively greater importance. This review will focus on the molecules of the extracellular matrix, specifically relating to vessel formation and their ability to signal to the surrounding cells to initiate or terminate processes involved in blood vessel formation.

Dermatology 75 Years Ago., Lawrence Parish, Joseph A Witkowski

Department of Dermatology and Cutaneous Biology Faculty Papers

It seems that the practicing dermatologist in 2007 is being attacked on all fronts. The Food and Drug Administration has mandated a cumbersome program for monitoring isotrentinoin usage, its analogue barely comes under scrutiny. iPledge is just a plain nightmare. The acumen of the board certified dermatologist is being challenged by Maintenance of Certification proposals because other specialties are doing it; yet, the neighborhood pharmacist is unhampered in dispensing all sorts of advice about treatment. The insurance clerk thrives on denying medication, prescribed by the physician, using flawed reasoning or else suggesting that a ten days’ supply of medicine should …

Alzheimer's Disease: Cholesterol, Membrane Rafts, Isoprenoids And Statins, Patrick C. Reid, Yasuomi Urano, Tatsuhiko Kodama, Takao Hamakubo

Dartmouth Scholarship

Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder and the most prevalent form of dementia worldwide. AD is characterized pathologically by amyloid-? plaques, neurofibrillary tangles and neuronal loss, and clinically by a progressive loss of cognitive abilities. At present, the fundamental molecular mechanisms underlying the disease are unclear and no treatment for AD is known. Epidemiological evidence continues to mount linking vascular diseases, such as hypertension and diabetes, and hypercholesterolaemia with an increased risk for developing AD. A growing amount of evidence suggests a mechanistic link between cholesterol metabolism in the brain and the formation of amyloid plaques in AD …

Expansion Of The Calcium Hypothesis Of Brain Aging And Alzheimer's Disease: Minding The Store, Olivier Thibault, John C. Gant, Philip W. Landfield

Pharmacology and Nutritional Sciences Faculty Publications

Evidence accumulated over more than two decades has implicated Ca2+ dysregulation in brain aging and Alzheimer's disease (AD), giving rise to the Ca2+ hypothesis of brain aging and dementia. Electrophysiological, imaging, and behavioral studies in hippocampal or cortical neurons of rodents and rabbits have revealed aging-related increases in the slow afterhyperpolarization, Ca2+ spikes and currents, Ca2+transients, and L-type voltage-gated Ca2+ channel (L-VGCC) activity. Several of these changes have been associated with age-related deficits in learning or memory. Consequently, one version of the Ca2+ hypothesis has been that increased L-VGCC activity drives many of the other Ca2+-related biomarkers of hippocampal aging. …

Functional Dissociation In Frontal And Striatal Areas For Processing Of Positive And Negative Reward Information, Xun Liu, David K. Powell, Hongbin Wang, Brian T. Gold, Christine R. Corbly, Jane E. Joseph

Neuroscience Faculty Publications

Reward-seeking behavior depends critically on processing of positive and negative information at various stages such as reward anticipation, outcome monitoring, and choice evaluation. Behavioral and neuropsychological evidence suggests that processing of positive (e.g., gain) and negative (e.g., loss) reward information may be dissociable and individually disrupted. However, it remains uncertain whether different stages of reward processing share certain neural circuitry in frontal and striatal areas, and whether distinct but interactive systems in these areas are recruited for positive and negative reward processing. To explore these issues, we used a monetary decision-making task to investigate the roles of frontal and striatal …

The Notch Regulator Maml1 Interacts With P53 And Functions As A Coactivator., Yongtong Zhao, Rebecca B. Katzman, Laurie M. Delmolino, Ishfaq Bhat, Ying Zhang, Channabasavaiah B. Gurumurthy, Aleksandra Germaniuk-Kurowska, Honey V. Reddi, Aharon Solomon, Mu-Sheng Zeng, Aisha Kung, Hui Ma, Qingshen Gao, Goberdhan Dimri, Adina Stanculescu, Lucio Miele, Lizi Wu, James D. Griffin, David E. Wazer, Hamid Band, Vimla Band

Journal Articles: Biochemistry & Molecular Biology

Members of the evolutionarily conserved Mastermind (MAM) protein family, including the three related mammalian Mastermind-like (MAML) proteins MAML1-3, function as crucial coactivators of Notch-mediated transcriptional activation. Given the recent evidence of cross-talk between the p53 and Notch signal transduction pathways, we have investigated whether MAML1 may also be a transcriptional coactivator of p53. Indeed, we show here that MAML1 is able to interact with p53. We show that MAML1-p53 interaction involves the N-terminal region of MAML1 and the DNA-binding domain of p53, and we use a chromatin immunoprecipitation assay to show that MAML1 is part of the activator complex that …

Phobias: The Evolutionary Trend, Grant Brown

Honors Capstones

Capstone submitted as a graduation requirement for the BSU Honors Program.

Clinical Implication Of Genome-Wide Profiling In Diffuse Large B-Cell Lymphoma And Other Subtypes Of B-Cell Lymphoma., Javeed Iqbal, Shantaram Joshi, Kavita N. Patel, Sofi I. Javed, Can Kucuk, Afeera Aabida, Francesco D'Amore, Kai Fu

Journal Articles: Pathology and Microbiology

The differentiation of lymphoid cells is tightly regulated by transcription factors at various stages during their development. During the maturation processes, different genomic alterations or aberrations such as chromosomal translocation, mutation and deletions may occur that can eventually result in distinct biological and clinical tumors. The different differentiation stages create heterogeneity in lymphoid malignancies, which can complicate the diagnosis. The initial diagnostic scheme for lymphoid diseases was coined by Rappaport followed by Revised European and American Classification of Lymphoid Neoplasms (REAL) and World Health Organization (WHO) classifications. These classification methods were based on histological, immunophenotypic and cytogenetic markers and widely …

The State Of The Art In Evaluating The Performance Of Department Chairs And Division Heads., David G. Dunning, Timothy M. Durham, Mert N. Aksu, Brian M. Lange

Journal Articles: College of Dentistry

This study explores the little understood process of evaluating the performance of department chairs/division heads in dental schools. Specifically, this research aimed to elucidate the methods, processes, and outcomes related to the job performance of department chairs/division heads. Forty-three deans and 306 chairs completed surveys with both close-ended and open-ended questions. In addition, ten deans and ten chairs were interviewed. Results indicate that 80 to 90 percent of department chairs are formally evaluated, although as many as 50 percent may lack job descriptions. Recommended best practices for performance appraisal--such as having at least yearly appraisals, holding face-to-face meetings, and setting …

A Pilot Study Of Atomoxetine In Young Children With Attention-Deficit/Hyperactivity Disorder., Christopher J. Kratochvil, Brigette S. Vaughan, Michelle L. Mayfield-Jorgensen, John S. March, Scott H. Kollins, Desiree W. Murray, Hima Ravi, Laurence L. Greenhill, Lisa A. Kotler, Natalya Paykina, Patricia Biggins, Julie Stoner

Journal Articles: Psychiatry

OBJECTIVE: The purpose of this study was to assess the effectiveness and tolerability of atomoxetine during acute treatment of attention-deficit/hyperactivity disorder (ADHD) in 5 and 6 year olds.

METHOD: Twenty two children (male n = 19, 86%) with ADHD were treated with atomoxetine for 8 weeks in a three-site, open-label pilot study. Dosing was flexible, with titration to a maximum of 1.8 mg/kg per day. Parent education on behavior management was provided as part of each pharmacotherapy visit.

RESULTS: Subjects demonstrated a mean decrease of 20.68 points (SD = 12.80, p < 0.001)) on the ADHD Rating Scale-IV (ADHD-IV-RS) total score, 10.18 (SD = 7.48, p < 0.001) on the inattentive subscale and 10.50 (SD = 7.04, p < 0.001) on the hyperactive/impulsive subscale. Clinical Global Impression-Severity (CGI-S) was improved in 82% of the children (95% CI, 66-98%) and Children's Global Assessment (CGAS) scores improved 18.91 points on average (SD = 12.20, p < 0.001). The mean final dose of atomoxetine was 1.25 mg/kg per day (SD = 0.35 mg/kg per day). Mood lability was the most commonly reported adverse event (n = 12, 54.5%). Eleven subjects (50%) reported decreased appetite and a mean weight loss of 1.04 kg (SD = 0.80 kg) (p < 0.001) was observed for the group. Vital sign changes were mild and not clinically significant. There were no discontinuations due to adverse events or lack of efficacy.

CONCLUSION: Atomoxetine was generally effective for reducing core ADHD …