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Tuberculosis Susceptibility And Vaccine Protection Are Independently Controlled By Host Genotype, Clare M. Smith, Megan K. Proulx, Andrew J. Olive, Dominick Laddy, Bibhuti B. Mishra, Caitlin Moss, Nuria Martinez, Michelle M. Bellerose, Palmira Barreira-Silva, Jia Yao Phuah, Richard E. Baker, Samuel M. Behar, Hardy Kornfeld, Thomas G. Evans, Gillian Beamer, Christopher M. Sassetti 2016 University of Massachusetts Medical School

Tuberculosis Susceptibility And Vaccine Protection Are Independently Controlled By Host Genotype, Clare M. Smith, Megan K. Proulx, Andrew J. Olive, Dominick Laddy, Bibhuti B. Mishra, Caitlin Moss, Nuria Martinez, Michelle M. Bellerose, Palmira Barreira-Silva, Jia Yao Phuah, Richard E. Baker, Samuel M. Behar, Hardy Kornfeld, Thomas G. Evans, Gillian Beamer, Christopher M. Sassetti

Open Access Articles

The outcome of Mycobacterium tuberculosis infection and the immunological response to the bacillus Calmette-Guerin (BCG) vaccine are highly variable in humans. Deciphering the relative importance of host genetics, environment, and vaccine preparation for the efficacy of BCG has proven difficult in natural populations. We developed a model system that captures the breadth of immunological responses observed in outbred individual mice, which can be used to understand the contribution of host genetics to vaccine efficacy. This system employs a panel of highly diverse inbred mouse strains, consisting of the founders and recombinant progeny of the "Collaborative Cross" project. Unlike natural populations ...


There Is A Trend Favoring Vancomycin Vs. Metronidazole In Treating Severe C. Difficile Infection, Dean D. Fouchia 2016 Wayne State University School of Medicine

There Is A Trend Favoring Vancomycin Vs. Metronidazole In Treating Severe C. Difficile Infection, Dean D. Fouchia

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Johnson S, Louie TJ, Gerding DN, et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014;59(3):345-354. doi: 10.1093/cid/ciu313


Dynamic Host-Pathogen Interactions Result In Fungal Epitope Unmasking, Alex Hopke 2016 University of Maine

Dynamic Host-Pathogen Interactions Result In Fungal Epitope Unmasking, Alex Hopke

Electronic Theses and Dissertations

Molecular camouflage is used by a diverse set of pathogens to disguise their identity and avoid recognition by protective host receptors. The opportunistic fungal pathogen Candida albicans is a good example, as it masks the inflammatory component β-glucan in its cell wall to evade detection by the immune receptor Dectin-1. Interestingly, it has been seen that β-glucan becomes unmasked during infection in vivo, though the underlying mechanisms remained unclear. Exposure levels of this epitope may be important, as Dectin-1 mediates protection from some strains of C. albicans and alterations in the organization and composition of the Candida cell wall can ...


Potency Of A Human Monoclonal Antibody To Diphtheria Toxin Relative To Equine Diphtheria Anti-Toxin In A Guinea Pig Intoxication Model, Heidi L. Smith, Peter S. Cheslock, Mark Leney, Bruce A. Barton, Deborah C. Molrine 2016 University of Massachusetts Medical School

Potency Of A Human Monoclonal Antibody To Diphtheria Toxin Relative To Equine Diphtheria Anti-Toxin In A Guinea Pig Intoxication Model, Heidi L. Smith, Peter S. Cheslock, Mark Leney, Bruce A. Barton, Deborah C. Molrine

Pediatric Publications and Presentations

Prompt administration of anti-toxin reduces mortality following Corynebacterium diphtheriae infection. Current treatment relies upon equine diphtheria anti-toxin (DAT), with a 10% risk of serum sickness and rarely anaphylaxis. The global DAT supply is extremely limited; most manufacturers have ceased production. S315 is a neutralizing human IgG1 monoclonal antibody to diphtheria toxin that may provide a safe and effective alternative to equine DAT and address critical supply issues. To guide dose selection for IND-enabling pharmacology and toxicology studies, we dose-ranged S315 and DAT in a guinea pig model of diphtheria intoxication based on the NIH Minimum Requirements potency assay. Animals received ...


The Activity Of Antimicrobial Surfaces Varies By Testing Protocol Utilized, Matias D. Campos, Paola C. Zucchi, Ann Phung, Steven N. Leonard, Elizabeth B. Hirsch 2016 Northeastern University

The Activity Of Antimicrobial Surfaces Varies By Testing Protocol Utilized, Matias D. Campos, Paola C. Zucchi, Ann Phung, Steven N. Leonard, Elizabeth B. Hirsch

Pharmacy Faculty Scholarship

Background: Contaminated hospital surfaces are an important source of nosocomial infections. A major obstacle in marketing antimicrobial surfaces is a lack of efficacy data based on standardized testing protocols. Aim: We compared the efficacy of multiple testing protocols against several “antimicrobial” film surfaces.

Methods: Four clinical isolates were used: one Escherichia coli, one Klebsiella pneumoniae, and two Staphylococcus aureus strains. Two industry methods (modified ISO 22196 and ASTM E2149), a “dried droplet”, and a “transfer” method were tested against two commercially available antimicrobial films, one film in development, an untreated control, and a positive (silver) control film. At 2 (only ...


Structural And Molecular Analysis Of A Protective Epitope Of Lyme Disease Antigen Ospa And Antibody Interactions, Shivender Shandilya, Nese Kurt Yilmaz, Ejemel Monir, Andrew Sadowski, William D. Thomas, Mark S. Klempner, Celia A. Schiffer, Yan Wang 2016 University of Massachusetts Medical School

Structural And Molecular Analysis Of A Protective Epitope Of Lyme Disease Antigen Ospa And Antibody Interactions, Shivender Shandilya, Nese Kurt Yilmaz, Ejemel Monir, Andrew Sadowski, William D. Thomas, Mark S. Klempner, Celia A. Schiffer, Yan Wang

Celia A. Schiffer

The murine monoclonal antibody LA-2 recognizes a clinically protective epitope on outer surface protein (OspA) of Borrelia burgdorferi, the causative agent of Lyme disease in North America. Human antibody equivalence to LA-2 is the best serologic correlate of protective antibody responses following OspA vaccination. Understanding the structural and functional basis of the LA-2 protective epitope is important for developing OspA-based vaccines and discovering prophylactic antibodies against Lyme disease. Here, we present a detailed structure-based analysis of the LA-2/OspA interaction interface and identification of residues mediating antibody recognition. Mutations were introduced into both OspA and LA-2 based on computational predictions ...


N-Methylation Of A Bactericidal Compound As A Resistance Mechanism In Mycobacterium Tuberculosis, Kenan C. Murphy, Carl F. Nathan 2016 University of Massachusetts Medical School

N-Methylation Of A Bactericidal Compound As A Resistance Mechanism In Mycobacterium Tuberculosis, Kenan C. Murphy, Carl F. Nathan

Open Access Articles

The rising incidence of antimicrobial resistance (AMR) makes it imperative to understand the underlying mechanisms. Mycobacterium tuberculosis (Mtb) is the single leading cause of death from a bacterial pathogen and estimated to be the leading cause of death from AMR. A pyrido-benzimidazole, 14, was reported to have potent bactericidal activity against Mtb. Here, we isolated multiple Mtb clones resistant to 14. Each had mutations in the putative DNA-binding and dimerization domains of rv2887, a gene encoding a transcriptional repressor of the MarR family. The mutations in Rv2887 led to markedly increased expression of rv0560c. We characterized Rv0560c as an S-adenosyl-L-methionine-dependent ...


Genomic Insights Into The Ixodes Scapularis Tick Vector Of Lyme Disease, Monika Gulia-Nuss,, Daniel R. Caffrey, Neal S. Silverman, Adam R. Wespiser, Catherine A. Hill 2016 Purdue University

Genomic Insights Into The Ixodes Scapularis Tick Vector Of Lyme Disease, Monika Gulia-Nuss,, Daniel R. Caffrey, Neal S. Silverman, Adam R. Wespiser, Catherine A. Hill

Neal Silverman

Ticks transmit more pathogens to humans and animals than any other arthropod. We describe the 2.1 Gbp nuclear genome of the tick, Ixodes scapularis (Say), which vectors pathogens that cause Lyme disease, human granulocytic anaplasmosis, babesiosis and other diseases. The large genome reflects accumulation of repetitive DNA, new lineages of retro-transposons, and gene architecture patterns resembling ancient metazoans rather than pancrustaceans. Annotation of scaffolds representing approximately 57% of the genome, reveals 20,486 protein-coding genes and expansions of gene families associated with tick-host interactions. We report insights from genome analyses into parasitic processes unique to ticks, including host 'questing ...


Endothelial Hspa12b Is A Novel Protein For The Preservation Of Cardiovascular Function In Polymicrobial Sepsis Via Exosome Mir-126, Xia Zhang 2016 East Tennessee State University

Endothelial Hspa12b Is A Novel Protein For The Preservation Of Cardiovascular Function In Polymicrobial Sepsis Via Exosome Mir-126, Xia Zhang

Electronic Theses and Dissertations

Sepsis is the most frequent cause of mortality in most intensive care units. Cardiovascular dysfunction is a major complication associated with sepsis, with high mortality rates up to 70%. Currently, there is no effective treatment approach for sepsis.

The integrity of the endothelium is fundamental for the homeostasis of the cardiovascular system. Sepsis induces endothelial cell injury which is the key factor for multiple organ failure. The increased expression of adhesion molecules and chemokines in endothelial cell promotes leukocytes infiltration into the tissue. The loss of tight junction proteins and increased permeability of the endothelial cells will provoke tissue hypoxia ...


Study Design Of A Cluster-Randomized Controlled Trial To Evaluate A Large-Scale Distribution Of Cook Stoves And Water Filters In Western Province, Rwanda, Corey L. Nagel, Miles Kirby, Laura D. Zambrano, Ghislaine Rosa, Christina K. Barstow, Evan A. Thomas, Thomas Clasen 2016 Oregon Health & Science University

Study Design Of A Cluster-Randomized Controlled Trial To Evaluate A Large-Scale Distribution Of Cook Stoves And Water Filters In Western Province, Rwanda, Corey L. Nagel, Miles Kirby, Laura D. Zambrano, Ghislaine Rosa, Christina K. Barstow, Evan A. Thomas, Thomas Clasen

Mechanical and Materials Engineering Faculty Publications and Presentations

Background: In Rwanda, pneumonia and diarrhea are the first and second leading causes of death, respectively, among children under five. Household air pollution (HAP) resultant from cooking indoors with biomass fuels on traditional stoves is a significant risk factor for pneumonia, while consumption of contaminated drinking water is a primary cause of diarrheal disease. To date, there have been no largescale effectiveness trials of programmatic efforts to provide either improved cookstoves or household water filters at scale in a low-income country. In this paper we describe the design of a clusterrandomized trial to evaluate the impact of a national-level program ...


Investigation Of Cnt-Induced Escherichia Coli Lysis And Protein Release, Abdollah Mosleh 2016 University of Arkansas, Fayetteville

Investigation Of Cnt-Induced Escherichia Coli Lysis And Protein Release, Abdollah Mosleh

Theses and Dissertations

This research investigated the use of carbon nanotubes (CNTs) as a treatment to increase the permeability of a bacterial cell wall. Recombinant Escherichia coli BL21 (DE3) containing a plasmid that expressed Green Fluorescent Protein (GFP) and -lactamase were exposed to CNTs under various levels of agitation for different times. Fluorescence assay for GFP, optical absorbance for -lactamase activity, and Transmission Electron Microscopy (TEM) were used to determine the amount of released protein, and visually examine the permeability enhancement of the cells, respectively. It was found that more -lactamase was present in the culture fluid after treatment with CNTs in a ...


Comparisons Of Selected Household And Commercial Disinfectants Against Poultry Salmonella Isolates And A Survey Of Internal Parasites In Backyard Poultry In Arkansas, Kayleigh Moyle 2016 University of Arkansas, Fayetteville

Comparisons Of Selected Household And Commercial Disinfectants Against Poultry Salmonella Isolates And A Survey Of Internal Parasites In Backyard Poultry In Arkansas, Kayleigh Moyle

Theses and Dissertations

Backyard and exhibition poultry have been gaining in popularity and as such there has been a large increase in the number of small flocks. As the interaction with poultry has increased, so has the opportunity for diseases and parasites, for both birds and people. One of the major zoonotic illnesses is caused by the bacteria Salmonella, which can be found in commercial and small flocks. Salmonella is the number 2 contributor of foodborne illnesses so its prevalence in commercial flocks is of high concern. Despite improved cleaning, disinfection, and biosecurity practices, there is still potential for disease outbreaks and infections ...


Fecal Transplant Vs Vancomycin For Recurrent Clostridium Diffile, Lauren M. Taylor, Todd E. Edwards 2016 James Madison University

Fecal Transplant Vs Vancomycin For Recurrent Clostridium Diffile, Lauren M. Taylor, Todd E. Edwards

Physician Assistant Capstones

Objective: To compare fecal transplant and vancomycin in the treatment of recurrent clostridium difficile to determine which has the higher cure rate. Design: Systematic literature review. Methods: Pubmed, Google Scholar, and TRIP database using the search terms “recurrent clostridium difficile.” Filters were implemented in the Pubmed database including: randomized control trials, English, and published in the past 5 years. Records were screened for RCT with fecal transplant and full-text. Results: van Nood et al. revealed an initial cure rate of 81% for the infusion group, and a re-treated cure rate of 94%, compared to the vancomycin alone group of 31 ...


Linezolid Induced Delirium In The Absence Of Serotonin Syndrome: A Psychiatric Consultation/Liaison Case Report, Hani Nazha, MD, Nathan T. Harrington, MD 2016 WVU

Linezolid Induced Delirium In The Absence Of Serotonin Syndrome: A Psychiatric Consultation/Liaison Case Report, Hani Nazha, Md, Nathan T. Harrington, Md

Marshall Journal of Medicine

Delirium is one of the most common mental illnesses that can affect elderly patients and patients with advanced medical problems. Because these patients are frequently on multiple medications and/or are more sensitive to medications secondary to their age, interactions with current medications, or existing medical problems; medication toxicity is frequently the etiology behind their delirium. This is a case report of a patient admitted for cellulitis that developed delirium from Linezolid however did not develop any other signs or symptoms of Serotonin Syndrome; a known side effect of Linezolid. This distinctive case highlights the importance of a careful analysis ...


Plague And The Defeat Of Mammalian Innate Immunity: Systematic Genetic Analysis Of Yersinia Pestis Virulence Factors: A Dissertation, Samantha G. Palace 2016 University of Massachusetts Medical School

Plague And The Defeat Of Mammalian Innate Immunity: Systematic Genetic Analysis Of Yersinia Pestis Virulence Factors: A Dissertation, Samantha G. Palace

GSBS Dissertations and Theses

Yersinia pestis, the causative agent of plague, specializes in causing dense bacteremia following intradermal deposition of a small number of bacteria by the bite of an infected flea. This robust invasiveness requires the ability to evade containment by the innate immune system. Of the various mechanisms employed by Y. pestis to subvert the innate immune response and to proliferate rapidly in mammalian tissue, only a few are well-characterized. Here, I present two complementary genetic analyses of Y. pestis adaptations to the mammalian environment. In the first, genome-wide fitness profiling for Y. pestis by Tn-seq demonstrates that the bacterium has adapted ...


Gram-Negative Bacteria And Sepsis, Christine D. Ridge 2016 Otterbein University

Gram-Negative Bacteria And Sepsis, Christine D. Ridge

Master of Science in Nursing (MSN) Student Scholarship

Today’s medical world encompasses an environment in which gram-negative bacteria that once were defeated with common antibiotics, have now become resistant. Gram-negative bacteria like Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter, and Acinetobacter are pathogens that are an emerging threat causing sepsis due to multidrug-resistance (Pop-Vicas & Opal, 2014, p.189). The multidrug-resistance mechanisms of gram-negative bacteria coupled with a patient population commonly seen in hospital settings, that consist of immunocompromised adults due to advancing age, comorbidities (e.g. AIDS, history of transplants, diabetes, and chemotherapy), and immunotherapies, create an environment for advanced infection or sepsis to take place.

Complications of multidrug-resistant ...


Memory Cd8+ T Cell Function During Mycobacterium Tuberculosis Infection: A Dissertation, Stephen M. Carpenter 2016 University of Massachusetts Medical School

Memory Cd8+ T Cell Function During Mycobacterium Tuberculosis Infection: A Dissertation, Stephen M. Carpenter

GSBS Dissertations and Theses

T cell vaccines against Mycobacterium tuberculosis (Mtb) and other pathogens are based on the principle that memory T cells rapidly generate effector responses upon challenge, leading to pathogen clearance. Despite eliciting a robust memory CD8+ T cell response to the immunodominant Mtb antigen TB10.4 (EsxH), we find the increased frequency of TB10.4-specific CD8+ T cells conferred by vaccination to be short-lived after Mtb challenge. To compare memory and naïve CD8+ T cell function during their response to Mtb, we track their expansions using TB10.4-specific retrogenic CD8+ T cells. We find that the primary (naïve) response outnumbers the ...


Type I Interferon Induction By Neisseria Gonorrhoeae: Dual Requirement Of Cyclic Gmp-Amp Synthase And Toll-Like Receptor 4, Warrison A. Andrade, Sarika Agarwal, Shunyan Mo, Scott A. Shaffer, Joseph P. Dillard, Tobias Schmidt, Veit Hornung, Katherine A. Fitzgerald, Evelyn A. Kurt-Jones, Douglas T. Golenbock 2016 University of Massachusetts Medical School

Type I Interferon Induction By Neisseria Gonorrhoeae: Dual Requirement Of Cyclic Gmp-Amp Synthase And Toll-Like Receptor 4, Warrison A. Andrade, Sarika Agarwal, Shunyan Mo, Scott A. Shaffer, Joseph P. Dillard, Tobias Schmidt, Veit Hornung, Katherine A. Fitzgerald, Evelyn A. Kurt-Jones, Douglas T. Golenbock

Open Access Articles

The innate immune system is the first line of defense against Neisseria gonorrhoeae (GC). Exposure of cells to GC lipooligosaccharides induces a strong immune response, leading to type I interferon (IFN) production via TLR4/MD-2. In addition to living freely in the extracellular space, GC can invade the cytoplasm to evade detection and elimination. Double-stranded DNA introduced into the cytosol binds and activates the enzyme cyclic-GMP-AMP synthase (cGAS), which produces 2'3'-cGAMP and triggers STING/TBK-1/IRF3 activation, resulting in type I IFN expression. Here, we reveal a cytosolic response to GC DNA that also contributes to type I ...


Calcium Phosphate As A Key Material For Socially Responsible Tissue Engineering, Vuk Uskoković, Victoria M. Wu 2016 Chapman University

Calcium Phosphate As A Key Material For Socially Responsible Tissue Engineering, Vuk Uskoković, Victoria M. Wu

Pharmacy Faculty Articles and Research

Socially responsible technologies are designed while taking into consideration the socioeconomic, geopolitical and environmental limitations of regions in which they will be implemented. In the medical context, this involves making therapeutic platforms more accessible and affordable to patients in poor regions of the world wherein a given disease is endemic. This often necessitates going against the reigning trend of making therapeutic nanoparticles ever more structurally complex and expensive. However, studies aimed at simplifying materials and formulations while maintaining the functionality and therapeutic response of their more complex counterparts seldom provoke a significant interest in the scientific community. In this review ...


The Effect Of Oral Antibiotics On The Development Of Community Acquired Clostridium Difficile Colitis In Medicare Beneficiaries, Charles M. Psoinos, Courtney E. Collins, M. Didem Ayturk, Julie Flahive, Frederick A. Anderson Jr., Heena Santry 2016 University of Massachusetts Medical School

The Effect Of Oral Antibiotics On The Development Of Community Acquired Clostridium Difficile Colitis In Medicare Beneficiaries, Charles M. Psoinos, Courtney E. Collins, M. Didem Ayturk, Julie Flahive, Frederick A. Anderson Jr., Heena Santry

UMass Center for Clinical and Translational Science Research Retreat

Clostridium difficile infection (CDI) is increasingly prevalent among community dwelling Americans. Older Americans are particularly vulnerable to community-acquired Clostridium difficile (CACD), in part to increasing use of antibiotics. We studied the association between outpatient antibiotics and CACD among Medicare beneficiaries.

Case-control study utilizing a 5% sample of Medicare beneficiaries (2009-2011). Patients with CACD severe enough to warrant hospitalization were identified by a primary diagnosis code for CDI and no exposure to a healthcare environment within 90-days of admission. 1,514 CACD cases were matched to ten controls each on birth year and sex. Potential controls with exposure to healthcare environment ...


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