Medicine and Health Sciences Commons^™

Serial Analysis Of The Gut And Respiratory Microbiome In Cystic Fibrosis In Infancy: Interaction Between Intestinal And Respiratory Tracts And Impact Of Nutritional Exposures, J. C. Madan, D. C. Koestler, B. A. Stanton, L. Davidson, L. A. Moulton, M. L. Housman, J. H. Moore, M. F. Guill, H. G. Morrison, M. L. Sogin, T. H. Hampton, M. R. Karagas, P. E. Palumbo, J. A. Foster, P. L. Hibberd, G. A. O’Toole

Dartmouth Scholarship

Pulmonary damage caused by chronic colonization of the cystic fibrosis (CF) lung by microbial communities is the proximal cause of respiratory failure. While there has been an effort to document the microbiome of the CF lung in pediatric and adult patients, little is known regarding the developing microflora in infants. We examined the respiratory and intestinal microbiota development in infants with CF from birth to 21 months. Distinct genera dominated in the gut compared to those in the respiratory tract, yet some bacteria overlapped, demonstrating a core microbiota dominated by Veillonella and Streptococcus. Bacterial diversity increased significantly over time, …

Attentive And Pre-Attentive Processes In Change Detection And Identification, Howard C. Hughes, Gideon Paul Caplovitz, Rebecca A. Loucks, Robert Fendrich

Dartmouth Scholarship

In studies of change blindness, observers often have the phenomenological impression that the blindness is overcome all at once, so that change detection, localization and identification apparently occur together. Three experiments are described that explore dissociations between these processes using a discrete trial procedure in which 2 visual frames are presented sequentially with no intervening inter-frame-interval. The results reveal that change detection and localization are essentially perfect under these conditions regardless of the number of elements in the display, which is consistent with the idea that change detection and localization are mediated by pre-attentive parallel processes. In contrast, identification accuracy …

Murine Gammaherpesvirus 68 Lana Acts On Terminal Repeat Dna To Mediate Episome Persistence, Aline C. Habison, Chantal Beauchemin, J. Pedro Simas, Edward J. Usherwood

Dartmouth Scholarship

Murine gammaherpesvirus 68 (MHV68) ORF73 (mLANA) has sequence homology to Kaposi’s sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA). LANA acts on the KSHV terminal repeat (TR) elements to mediate KSHV episome maintenance. Disruption of mLANA expression severely reduces the ability of MHV68 to establish latent infection in mice, consistent with the possibility that mLANA mediates episome persistence. Here we assess the roles of mLANA and MHV68 TR (mTR) elements in episome persistence. mTR-associated DNA persisted as an episome in latently MHV68-infected tumor cells, demonstrating that the mTR elements can serve as a cis-acting element for MHV68 episome maintenance. In some …

Microbiological Components In Mainstream And Sidestream Cigarette Smoke, Lennart Larsson, Christina Pehrson, Tenzin Dechen, Mardi Crane-Godreau

Dartmouth Scholarship

Research has shown that tobacco smoke contains substances of microbiological origin such as ergosterol (a fungal membrane lipid) and lipopolysaccharide (LPS) (in the outer membrane of Gram-negative bacteria). The aim of the present study was to compare the amounts of ergosterol and LPS in the tobacco and mainstream (MS) and sidestream (SS) smoke of some popular US cigarettes. We measured LPS 3-hydroxy fatty acids and fungal biomass biomarker ergosterol in the tobacco and smoke from cigarettes of 11 popular brands purchased in the US. University of Kentucky reference cigarettes were also included for comparison.

The Crispr/Cas Adaptive Immune System Of Pseudomonas Aeruginosa Mediates Resistance To Naturally Occurring And Engineered Phages, Kyle C. Cady, Joe Bondy-Denomy, Gary E. Heussler, Alan R. Davidson, George A. O'Toole

Dartmouth Scholarship

Here we report the isolation of 6 temperate bacteriophages (phages) that are prevented from replicating within the laboratory strain Pseudomonas aeruginosa PA14 by the endogenous CRISPR/Cas system of this microbe. These phages are only the second identified group of naturally occurring phages demonstrated to be blocked for replication by a nonengineered CRISPR/Cas system, and our results provide the first evidence that the P. aeruginosa type I-F CRISPR/Cas system can function in phage resistance. Previous studies have highlighted the importance of the protospacer adjacent motif (PAM) and a proximal 8-nucleotide seed sequence in mediating CRISPR/Cas-based immunity. Through engineering of a protospacer …

Coronary Heart Disease In Primary Care: Accuracy Of Medical History And Physical Findings In Patients With Chest Pain – A Study Protocol For A Systematic Review With Individual Patient Data, Jörg Haasenritter, Marc Aerts, Stefan Bösner, Frank Buntinx, Bernard Burnand, Lilli Herzig, J André Knottnerus, Girma Minalu, Staffan Nilsson, Walter Renier, Carol Sox, Carol Sox, Harold Sox, Norbert Donner-Banzhoff

Dartmouth Scholarship

Chest pain is a common complaint in primary care, with coronary heart disease (CHD) being the most concerning of many potential causes. Systematic reviews on the sensitivity and specificity of symptoms and signs summarize the evidence about which of them are most useful in making a diagnosis. Previous meta-analyses are dominated by studies of patients referred to specialists. Moreover, as the analysis is typically based on study-level data, the statistical analyses in these reviews are limited while meta-analyses based on individual patient data can provide additional information. Our patient-level meta-analysis has three unique aims. First, we strive to determine the …

A Digital X-Ray Tomosynthesis Coupled Near Infrared Spectral Tomography System For Dual-Modality Breast Imaging, Venkataramanan Krishnaswamy, Kelly E. Michaelsen, Brian W. Pogue, Steven P. Poplack, Ian Shaw, Ken Defrietas, Ken Brooks, Keith D. Paulsen

Dartmouth Scholarship

A Near Infrared Spectral Tomography (NIRST) system has been developed and integrated into a commercial Digital Breast Tomosynthesis (DBT) scanner to allow structural and functional imaging of breast in vivo. The NIRST instrument uses an 8-wavelength continuous wave (CW) laser-based scanning source assembly and a 75-element silicon photodiode solid-state detector panel to produce dense spectral and spatial projection data from which spectrally constrained 3D tomographic images of tissue chromophores are produced. Integration of the optical imaging system into the DBT scanner allows direct co-registration of the optical and DBT images, while also facilitating the synergistic use of x-ray contrast as …

Minor Pilins Of The Type Iv Pilus System Participate In The Negative Regulation Of Swarming Motility, S L. Kuchma, E. F. Griffin, G. A. O'Toole

Dartmouth Scholarship

Pseudomonas aeruginosa exhibits distinct surface-associated behaviors, including biofilm formation, flagellum-mediated swarming motility, and type IV pilus-driven twitching. Here, we report a role for the minor pilins, PilW and PilX, components of the type IV pilus assembly machinery, in the repression of swarming motility. Mutating either the pilW or pilX gene alleviates the inhibition of swarming motility observed for strains with elevated levels of the intracellular signaling molecule cyclic di-GMP (c-di-GMP) due to loss of BifA, a c-di-GMP-degrading phosphodiesterase. Blocking PilD peptidase-mediated processing of PilW and PilX renders the unprocessed proteins defective for pilus assembly but still functional in c-di-GMP-mediated swarming …

Iron Homeostasis During Cystic Fibrosis Pulmonary Exacerbation, Alex H. Gifford, Lisa A. Moulton, Dana B. Dorman, Gordana Olbina, Mark Westerman, H. Worth Parker, Bruce Stanton, George A. O'Toole

Dartmouth Scholarship

BACKGROUND:

Hypoferremia is a marker of disease severity in cystic fibrosis (CF). The effect of systemic antibiotics on iron homeostasis during CF pulmonary exacerbation (CFPE) is unknown. Our central hypotheses were that, by the completion of treatment, serum iron would increase, serum concentrations of interleukin-6 (IL-6) and hepcidin-25, two mediators of hypoferremia, would decrease, and sputum iron would decrease.

METHODS:

Blood and sputum samples were collected from 12 subjects with moderate-to-severe CF (median percentage-predicted forced expiratory volume in 1 second (FEV(1) %) = 29%; median weight = 56 kg) within 24 hours of starting and completing a course of systemic …

Who Wears Me? Bioimpedance As A Passive Biometric, Cory Cornelius, Jacob Sorber, Ronald Peterson, Joe Skinner, Ryan Halter, David Kotz

Dartmouth Scholarship

Mobile and wearable systems for monitoring health are becoming common. If such an mHealth system knows the identity of its wearer, the system can properly label and store data collected by the system. Existing recognition schemes for such mobile applications and pervasive devices are not particularly usable – they require ıt active engagement with the person (e.g., the input of passwords), or they are too easy to fool (e.g., they depend on the presence of a device that is easily stolen or lost). \par We present a wearable sensor to passively recognize people. Our sensor uses the unique electrical properties …

Measurement Of The Oxidation State Of Mitochondrial Cytochrome C From The Neocortex Of The Mammalian Brain, Y. Sakata, M. Abajian, M. O. Ripple, R. Springett

Dartmouth Scholarship

Diffuse optical remission spectra from the mammalian neocortex at visible wavelengths contain spectral features originating from the mitochondria. A new algorithm is presented, based on analytically relating the first differential of the attenuation spectrum to the first differential of the chromophore spectra, that can separate and calculate the oxidation state of cytochrome c as well as the absolute concentration and saturation of hemoglobin. The algorithm is validated in phantoms and then tested on the neocortex of the rat during an anoxic challenge. Implementation of the algorithm will provide detailed information of mitochondrial oxygenation and mitochondrial function in physiological studies of …

Refining The Global Spatial Limits Of Dengue Virus Transmission By Evidence-Based Consensus, Oliver J. Brady, Peter W. Gething, Samir Bhatt, Jane P. Messina, John S. Brownstein, Anne G. Hoen

Dartmouth Scholarship

Background: Dengue is a growing problem both in its geographical spread and in its intensity, and yet current global distribution remains highly uncertain. Challenges in diagnosis and diagnostic methods as well as highly variable national health systems mean no single data source can reliably estimate the distribution of this disease. As such, there is a lack of agreement on national dengue status among international health organisations. Here we bring together all available information on dengue occurrence using a novel approach to produce an evidence consensus map of the disease range that highlights nations with an uncertain dengue status.

Methods/Principle Findings: …

Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens And Patient Outcomes: An Individual Patient Data Meta-Analysis Of 9,153 Patients, Shama D. Ahuja, David Ashkin, Monika Avendano, Rita Banerjee, Melissa Bauer, Jamie N. Bayona

Dartmouth Scholarship

Dick Menzies and colleagues report findings from a collaborative, individual patient-level meta-analysis of treatment outcomes among patients with multidrug-resistant tuberculosis.

Background: Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB.

A Comparison Of Individual Versus Community Influences On Youth Smoking Behaviours: A Cross-Sectional Observational Study, Anna M. Adachi-Mejia, Heather A. Carlos, Ethan M. Berke, Susanne E. Tanski, James Sargent

Dartmouth Scholarship

Objectives: To compare individual with community risk factors for adolescent smoking. Design: A cross-sectional observational study with multivariate analysis.Setting: National telephone survey.Participants: 3646 US adolescents aged 13–18 years in 2007 recruited through a random digit-dial survey.

Epoxide-Mediated Cifr Repression Of Cif Gene Expression Utilizes Two Binding Sites In Pseudomonas Aeruginosa, Alicia E. Ballok, Christopher D. Bahl, Emily L. Dolben, Allia K. Lindsay, Jessica D. St. Laurent, Deborah Hogan, Dean Madden, George A. O'Toole

Dartmouth Scholarship

Pseudomonas aeruginosa secretes an epoxide hydrolase virulence factor that reduces the apical membrane expression of ABC transporters such as the cystic fibrosis transmembrane conductance regulator (CFTR). This virulence factor, named CFTR inhibitory factor (Cif), is regulated by a TetR-family, epoxide-responsive repressor known as CifR via direct binding and repression. We identified two sites of CifR binding in the intergenic space between cifR and morB, the first gene in the operon containing the cif gene. We have mapped these binding sites and found they are 27 bp in length, and they overlap the -10 and +1 sites of both the cifR …

Measurement Of A Model Of Implementation For Health Care: Toward A Testable Theory, Joan M. Cook, Casey O'Donnell, Stephanie Dinnen, James C. Coyne, Josef I. Ruzek, Paula P. Schnurr

Dartmouth Scholarship

Greenhalgh et al. used a considerable evidence-base to develop a comprehensive model of implementation of innovations in healthcare organizations [1]. However, these authors did not fully operationalize their model, making it difficult to test formally. The present paper represents a first step in operationalizing Greenhalgh et al.'s model by providing background, rationale, working definitions, and measurement of key constructs.A systematic review of the literature was conducted for key words representing 53 separate sub-constructs from six of the model's broad constructs. Using an iterative process, we reviewed existing measures and utilized or adapted items. Where no one measure was deemed appropriate, …

Prevalence Of Streptococci And Increased Polymicrobial Diversity Associated With Cystic Fibrosis Patient Stability, L. M. Filkins, T. H. Hampton, A. H. Gifford, M. J. Gross, D. A. Hogan, M. L. Sogin, H. G. Morrison, B. J. Paster, G. A. O'Toole

Dartmouth Scholarship

Diverse microbial communities chronically colonize the lungs of cystic fibrosis patients. Pyrosequencing of amplicons for hypervariable regions in the 16S rRNA gene generated taxonomic profiles of bacterial communities for sputum genomic DNA samples from 22 patients during a state of clinical stability (outpatients) and 13 patients during acute exacerbation (inpatients). We employed quantitative PCR (qPCR) to confirm the detection of Pseudomonas aeruginosa and Streptococcus by the pyrosequencing data and human oral microbe identification microarray (HOMIM) analysis to determine the species of the streptococci identified by pyrosequencing. We show that outpatient sputum samples have significantly higher bacterial diversity than inpatients, but …

Associations Between Toenail Arsenic Concentration And Dietary Factors In A New Hampshire Ppopulation, Joann F. Gruber, Margaret R. Karagas, Diane Gilbert-Diamond, Pamela J. Bagley, M Scot Zens, Vicki Sayarath, Tracy Punshon, J Steven Morris, Kathryn L. Cottingham

Dartmouth Scholarship

Background: Dietary factors such as folate, vitamin B12, protein, and methionine are important for the excretion of arsenic via one-carbon metabolism in undernourished populations exposed to high levels of arsenic via drinking water. However, the effects of dietary factors on toenail arsenic concentrations in well-nourished populations exposed to relatively low levels of water arsenic are unknown.

Methods: As part of a population-based case-control study of skin and bladder cancer from the USA, we evaluated relationships between consumption of dietary factors and arsenic concentrations in toenail clippings. Consumption of each dietary factor was determined from a validated food frequency questionnaire. We …

Two Boundaries Separate Borrelia Burgdorferi Populations In North America, Gabriele Margos, Jean I. Tsao, Santiago Castillo-Ramirez, Yvette A. Girard, Anne G. Hoen

Dartmouth Scholarship

Understanding the spread of infectious diseases is crucial for implementing effective control measures. For this, it is important to obtain information on the contemporary population structure of a disease agent and to infer the evolutionary processes that may have shaped it. Here, we investigate on a continental scale the population structure of Borrelia burgdorferi, the causative agent of Lyme borreliosis (LB), a tick-borne disease, in North America. We test the hypothesis that the observed d population structure is congruent with recent population expansions and that these were preceded by bottlenecks mostly likely caused by the near extirpation in the 1900s …

The Prevalence And Characteristics Of Suicidality In Hiv/Aids As Seen In An African Population In Entebbe District, Uganda, Eugene Kinyanda, Susan Hoskins, Juliet Nakku, Saira Nawaz, Vikram Patel

Dartmouth Scholarship

Suicidality in HIV/AIDS is not only a predictor of future attempted suicide and completed suicide, it is also associated with poor quality of life and poor adherence with antiretroviral therapy. This paper examines the prevalence and correlates of suicidality in HIV/AIDS in the African nation of Uganda.

Cofactor Molecules Maintain Infectious Conformation And Restrict Strain Properties In Purified Prions, Nathan R. Deleault, Daniel J. Walsh, Justin R. Piro, Fei Wang, Xinhe Wang, Jiyan Ma, Judy R. Rees, Surachai Supattapone

Dartmouth Scholarship

No abstract provided.

Lapg, Required For Modulating Biofilm Formation By Pseudomonas Fluorescens Pf0-1, Is A Calcium-Dependent Protease, Chelsea D. Boyd, Debashree Chatterjee, Holger Sondermann, George A. O'Toole

Dartmouth Scholarship

Biofilm formation by Pseudomonas fluorescens Pf0-1 requires the cell surface adhesin LapA. We previously reported that LapG, a periplasmic cysteine protease of P. fluorescens, cleaves the N terminus of LapA, thus releasing this adhesin from the cell surface and resulting in loss of the ability to make a biofilm. The activity of LapG is regulated by the inner membrane-localized cyclic-di-GMP receptor LapD via direct protein-protein interactions. Here we present chelation and metal add-back studies demonstrating that calcium availability regulates biofilm formation by P. fluorescens Pf0-1. The determination that LapG is a calcium-dependent protease, based on in vivo and in vitro …

Med5(Nut1) And Med17(Srb4) Are Direct Targets Of Mediator Histone H4 Tail Interactions, Zhongle Liu, Lawrence C. Myers

Dartmouth Scholarship

The Mediator complex transmits activation signals from DNA bound transcription factors to the core transcription machinery. In addition to its canonical role in transcriptional activation, recent studies have demonstrated that S. cerevisiae Mediator can interact directly with nucleosomes, and their histone tails. Mutations in Mediator subunits have shown that Mediator and certain chromatin structures mutually impact each other structurally and functionally in vivo. We have taken a UV photo cross-linking approach to further delineate the molecular basis of Mediator chromatin interactions and help determine whether the impact of certain Mediator mutants on chromatin is direct. Specifically, by using histone …

Selective Impact Of Hiv Disease Progression On The Innate Immune System In The Human Female Reproductive Tract, Timothy Lahey, Mimi Ghosh, John V. Fahey, Zheng Shen, Lucy R. Mukura, Yan Song, Susan Cu-Uvin, Kenneth H. Mayer, Peter F. Wright, John C. Kappes, Christina Ochsenbauer, Charles R. Wira

Dartmouth Scholarship

Background: We have previously demonstrated intrinsic anti-HIV activity in cervicovaginal lavage (CVL) from HIV-infected women with high CD4 counts and not on antiretroviral therapy. However, the impact of HIV disease progression on CVL innate immune responses has not been delineated.

Methods: CVL from 57 HIV-infected women not on antiretroviral therapy were collected by washing the cervicovaginal area with 10 ml of sterile normal saline. We characterized subject HIV disease progression by CD4 count strata: >500 cells/µl, 200-500 cells/µl, or <200 cells/µl of blood. To assess CVL anti-HIV activity, we incubated TZM-bl cells with HIV plus or minus CVL. Antimicrobials, cytokines, chemokines and anti-gp160 HIV IgG antibodies were measured by ELISA and Luminex.

Evidence On The Human Health Effects Of Low-Level Methylmercury Exposure, Margaret R. Karagas, Anna L. Choi, Emily Oken, Milena Horvat, Rita Schoeny, Elizabeth Kamai, Whitney Cowell, Philippe Grandjean, Susan Korrick

Dartmouth Scholarship

Background: Methylmercury (MeHg) is a known neuro-toxicant. Emerging evidence indicates it may have adverse effects on the neuro-logic and other body systems at common low levels of exposure. Impacts of MeHg exposure could vary by individual susceptibility or be confounded by bene-ficial nutrients in fish containing MeHg. Despite its global relevance, synthesis of the available literature on low-level MeHg exposure has been limited.

Objectives: We undertook a synthesis of the current knowledge on the human health effects of low-level MeHg exposure to provide a basis for future research efforts, risk assessment, and exposure remediation policies worldwide.

Data sources and extraction: …

Effects Of Low-Dose Drinking Water Arsenic On Mouse Fetal And Postnatal Growth And Development, Courtney D. Kozul-Horvath, Fokko Zandbergen, Brian P. Jackson, Richard I. Enelow, Joshua W. Hamilton

Dartmouth Scholarship

Background: Arsenic (As) exposure is a significant worldwide environmental health concern. Chronic exposure via contaminated drinking water has been associated with an increased incidence of a number of diseases, including reproductive and developmental effects. The goal of this study was to identify adverse outcomes in a mouse model of early life exposure to low-dose drinking water As (10 ppb, current U.S. EPA Maximum Contaminant Level). Methodology and Findings: C57B6/J pups were exposed to 10 ppb As, via the dam in her drinking water, either in utero and/or during the postnatal period. Birth outcomes, the growth of the F1 offspring, and …

Molecular Epidemiology Of Hiv-Associated Tuberculosis In Dar Es Salaam, Tanzania: Strain Predominance, Clustering, And Polyclonal Disease, Lisa V. Adams, Barry N. Kreiswirth, Robert D. Arbeit, Hanna Soini, Lillian Mtei, Mecky Matee, Muhammad Bakari, Timothy Lahey, Wendy Wieland-Alter

Dartmouth Scholarship

Molecular typing of Mycobacterium tuberculosis can be used to elucidate the epidemiology of tuberculosis, including the rates of clustering, the frequency of polyclonal disease, and the distribution of genotypic families. We performed IS6110 typing and spoligotyping on M. tuberculosis strains isolated from HIV-infected subjects at baseline or during follow-up in the DarDar Trial in Tanzania and on selected community isolates. Clustering occurred in 203 (74%) of 275 subjects: 124 (80%) of 155 HIV-infected subjects with baseline isolates, 56 (69%) of 81 HIV-infected subjects with endpoint isolates, and 23 (59%) of 39 community controls. Overall, 113 (41%) subjects had an …

Isolation Of Phosphatidylethanolamine As A Solitary Cofactor For Prion Formation In The Absence Of Nucleic Acids, Nathan R. Deleault, Justin R. Piro, Daniel J. Walsh, Fei Wang, Jiyan Ma, James C. Geoghegan, Surachai Supattapone

Dartmouth Scholarship

Infectious prions containing the pathogenic conformer of the mammalian prion protein (PrP(Sc)) can be produced de novo from a mixture of the normal conformer (PrP(C)) with RNA and lipid molecules. Recent reconstitution studies indicate that nucleic acids are not required for the propagation of mouse prions in vitro, suggesting the existence of an alternative prion propagation cofactor in brain tissue. However, the identity and functional properties of this unique cofactor are unknown. Here, we show by purification and reconstitution that the molecule responsible for the nuclease-resistant cofactor activity in brain is endogenous phosphatidylethanolamine (PE). Synthetic PE alone facilitates conversion of …

Achieving High Coverage In Rwanda's National Human Papillomavirus Vaccination Programme, Agnes Binagwaho, Claire Wagner, Maurice Gatera, Corine Karema, Cameron T. Nutt, Fidele Ngabo

Dartmouth Scholarship

Problem: Virtually all women who have cervical cancer are infected with the human papillomavirus (HPV). Of the 275000 women who die from cervical cancer every year, 88% live in developing countries. Two vaccines against the HPV have been approved. However, vaccine implementation in low-income countries tends to lag behind implementation in high-income countries by 15 to 20 years.

Approach: In 2011, Rwanda’s Ministry of Health partnered with Merck to offer the Gardasil HPV vaccine to all girls of appropriate age. The Ministry formed a “public–private community partnership” to ensure effective and equitable delivery.

Local setting: Thanks to a strong national …

Propentofylline Targets Troy, A Novel Microglial Signaling Pathway, Valerie L. Jacobs, Yingna Liu, Joyce A. De Leo

Dartmouth Scholarship

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain cancer, with a median survival of less than 2 years after diagnosis with current available therapies. The tumor microenvironment serves a critical role in tumor invasion and progression, with microglia as a critical player. Our laboratory has previously demonstrated that propentofylline, an atypical methylxanthine with central nervous system glial modulating and anti-inflammatory actions, significantly decreases tumor growth in a GBM rodent model by preferentially targeting microglia. In the present study, we used the CNS-1 rat glioma model to elucidate the mechanisms of propentofylline. Here we demonstrate that propentofylline targets …