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Search Results: 1 - 10 of 270277 matches for " David R Herndon "
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Comparative genomic analysis and phylogenetic position of Theileria equi
Kappmeyer Lowell S,Thiagarajan Mathangi,Herndon David R,Ramsay Joshua D
BMC Genomics , 2012, DOI: 10.1186/1471-2164-13-603
Abstract: Background Transmission of arthropod-borne apicomplexan parasites that cause disease and result in death or persistent infection represents a major challenge to global human and animal health. First described in 1901 as Piroplasma equi, this re-emergent apicomplexan parasite was renamed Babesia equi and subsequently Theileria equi, reflecting an uncertain taxonomy. Understanding mechanisms by which apicomplexan parasites evade immune or chemotherapeutic elimination is required for development of effective vaccines or chemotherapeutics. The continued risk of transmission of T. equi from clinically silent, persistently infected equids impedes the goal of returning the U. S. to non-endemic status. Therefore comparative genomic analysis of T. equi was undertaken to: 1) identify genes contributing to immune evasion and persistence in equid hosts, 2) identify genes involved in PBMC infection biology and 3) define the phylogenetic position of T. equi relative to sequenced apicomplexan parasites. Results The known immunodominant proteins, EMA1, 2 and 3 were discovered to belong to a ten member gene family with a mean amino acid identity, in pairwise comparisons, of 39%. Importantly, the amino acid diversity of EMAs is distributed throughout the length of the proteins. Eight of the EMA genes were simultaneously transcribed. As the agents that cause bovine theileriosis infect and transform host cell PBMCs, we confirmed that T. equi infects equine PBMCs, however, there is no evidence of host cell transformation. Indeed, a number of genes identified as potential manipulators of the host cell phenotype are absent from the T. equi genome. Comparative genomic analysis of T. equi revealed the phylogenetic positioning relative to seven apicomplexan parasites using deduced amino acid sequences from 150 genes placed it as a sister taxon to Theileria spp. Conclusions The EMA family does not fit the paradigm for classical antigenic variation, and we propose a novel model describing the role of the EMA family in persistence. T. equi has lost the putative genes for host cell transformation, or the genes were acquired by T. parva and T. annulata after divergence from T. equi. Our analysis identified 50 genes that will be useful for definitive phylogenetic classification of T. equi and closely related organisms.
Reduction of Beta-Lactam Antimicrobial Activity in Staphylococcus aureus Abscesses by Neutrophil Alteration of Penicillin-Binding Protein 2  [PDF]
David M. Bamberger, Matthew Goers, Tim Quinn, Betty Herndon
Advances in Infectious Diseases (AID) , 2012, DOI: 10.4236/aid.2012.22007
Abstract: We previously demonstrated that brief nonkilling neutrophil exposure diminishes the binding affinity of S. aureus penicillin-binding protein (PBP) 2. We sought to investigate further the role of the neutrophil in the alteration of antimicrobial activity and its interaction with PBP-2 by studying the activity of cefotaxime, which highly binds to PBP 2, and cephalexin, which minimally binds to PBP 2. Using S. aureus, cultured in vitro in sterile-filtered normal and neutrophil depleted abscess fluid, we sought to demonstrate an in vivo significance of the neutrophil effect upon the activity of antimicrobials that target PBP-2 by studying the same antimicrobials in an experimental S. aureus abscess. Rats were implanted with perforated tissue cages and infected with S. aureus; some rats were neutrophil depleted by mechlorethamine. Abscess fluids from normal and neutropenic abscesses were harvested, pooled, sterile-filtered and stored for the time-kill studies. Treatment studies were performed by administering either 300 μg/kg/d cefotaxime or cephalexin for 7 days in other rats with 24 hour-old tissue-cage S. aureus abscesses. In time-kill studies, cefotaxime was highly active against stationary phase S. aureus in MHB and in neutropenic abscess fluid, but less active in the non-neutropenic abscess fluid (p < 0.05 compared to neutropenic abscess fluid). Cephalexin was equally active in neutropenic and non-noneutropenic abscess fluids, and more active than cefotaxime in the abscess model after 7 days of therapy (2.1 ± 1.7 log10 kill, p = 0.029 vs. 0.81 ± 2.5, p = NS). These data suggest that neutrophil exposure, which diminishes S. aureus PBP-2 binding affinity [or total quantity], also adversely affects the antimicrobial activity of cefotaxime, which binds to PBP-2, as compared to cephalexin. Altered PBP targets from neutrophil exposure may be a mechanism of antimicrobial resistance within abscesses.
A Divergent Artiodactyl MYADM-like Repeat Is Associated with Erythrocyte Traits and Weight of Lamb Weaned in Domestic Sheep
Michael V. Gonzalez, Michelle R. Mousel, David R. Herndon, Yu Jiang, Brian P. Dalrymple, James O. Reynolds, Wendell C. Johnson, Lynn M. Herrmann-Hoesing, Stephen N. White
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074700
Abstract: A genome-wide association study (GWAS) was performed to investigate seven red blood cell (RBC) phenotypes in over 500 domestic sheep (Ovis aries) from three breeds (Columbia, Polypay, and Rambouillet). A single nucleotide polymorphism (SNP) showed genome-wide significant association with increased mean corpuscular hemoglobin concentration (MCHC, P = 6.2×10?14) and genome-wide suggestive association with decreased mean corpuscular volume (MCV, P = 2.5×10?6). The ovine HapMap project found the same genomic region and the same peak SNP has been under extreme historical selective pressure, demonstrating the importance of this region for survival, reproduction, and/or artificially selected traits. We observed a large (>50 kb) variant haplotype sequence containing a full-length divergent artiodactyl MYADM-like repeat in strong linkage disequilibrium with the associated SNP. MYADM gene family members play roles in membrane organization and formation in myeloid cells. However, to our knowledge, no member of the MYADM gene family has been identified in development of morphologically variant RBCs. The specific RBC differences may be indicative of alterations in morphology. Additionally, erythrocytes with altered morphological structure often exhibit increased structural fragility, leading to increased RBC turnover and energy expenditure. The divergent artiodactyl MYADM-like repeat was also associated with increased ewe lifetime kilograms of lamb weaned (P = 2×10?4). This suggests selection for normal RBCs might increase lamb weights, although further validation is required before implementation in marker-assisted selection. These results provide clues to explain the strong selection on the artiodactyl MYADM-like repeat locus in sheep, and suggest MYADM family members may be important for RBC morphology in other mammals.
Conservation in the face of diversity: multistrain analysis of an intracellular bacterium
Michael J Dark, David R Herndon, Lowell S Kappmeyer, Mikel P Gonzales, Elizabeth Nordeen, Guy H Palmer, Donald P Knowles, Kelly A Brayton
BMC Genomics , 2009, DOI: 10.1186/1471-2164-10-16
Abstract: These comparisons revealed that A. marginale has a closed-core genome with few highly plastic regions, which include the msp2 and msp3 genes, as well as the aaap locus. Comparison of the Florida and St. Maries genome sequences found that SNPs comprise 0.8% of the longer Florida genome, with 33.5% of the total SNPs between all five strains present in at least two strains and 3.0% of SNPs present in all strains except Florida. Comparison of genomes from three strains of Mycobacterium tuberculosis, Bacillus anthracis, and Nessieria meningiditis, as well as four Chlamydophila pneumoniae strains found that 98.8%–100% of SNPs are unique to each strain, suggesting A. marginale, with 76.0%, has an intermediate level of strain-specific SNPs. Comparison of genomes from other organisms revealed variation in diversity that did not segregate with the environmental niche the bacterium occupies, ranging from 0.00% to 8.00% of the larger pairwise-compared genome.Analysis of multiple A. marginale strains suggests intracellular bacteria have more variable SNP retention rates than previously reported, and may have closed-core genomes in response to the host organism environment and/or reductive evolution.While the recent boom in genome sequencing projects has provided a wealth of information about bacterial metabolism and evolution, we know little about interstrain variation. A firm understanding of the rates and sites of variation is useful in determining genotypic differences associated with phenotypic traits and in formulating control strategies for a number of pathogens. Further, knowledge about the pan-genome of organisms will aid in determining the core genomic requirements, as well as shed more light on events that occur in the various environmental niches bacteria occupy.Most studies of bacterial diversity to date have either utilized specific genomic loci [1,2] or have examined metagenomics of specific environmental niches [3,4]. While these types of studies help elucidate th
Postnatal Imaging of Antenatal Hydronephrosis
David M. Kitchens,C. D. Anthony Herndon
The Scientific World Journal , 2009, DOI: 10.1100/tsw.2009.50
Prenatal Intervention for Lower Urinary Tract Obstruction
David M. Kitchens,C. D. Anthony Herndon
The Scientific World Journal , 2009, DOI: 10.1100/tsw.2009.49
PPAR-α agonism improves whole body and muscle mitochondrial fat oxidation, but does not alter intracellular fat concentrations in burn trauma children in a randomized controlled trial
Melanie G Cree, Bradley R Newcomer, David N Herndon, Ting Qian, Dayoung Sun, Beatrice Morio, Jennifer J Zwetsloot, G Lynis Dohm, Ricki Y Fram, Ronald P Mlcak, Asle Aarsland, Robert R Wolfe
Nutrition & Metabolism , 2007, DOI: 10.1186/1743-7075-4-9
Abstract: A double blind placebo controlled trial was conducted in 18 children with severe burn injury. Metabolic studies to assess whole body palmitate oxidation and insulin sensitivity, muscle biopsies for mitochondrial palmitate oxidation, diacylglycerol, fatty acyl Co-A and fatty acyl carnitine concentrations, and magnetic resonance spectroscopy for muscle and liver triglycerides were compared before and after two weeks of placebo or PPAR-α agonist treatment.Insulin sensitivity and basal whole body palmitate oxidation as measured with an isotope tracer increased significantly (P = 0.003 and P = 0.004, respectively) after PPAR-α agonist treatment compared to placebo. Mitochondrial palmitate oxidation rates in muscle samples increased significantly after PPAR-α treatment (P = 0.002). However, the concentrations of muscle triglyceride, diacylglycerol, fatty acyl CoA, fatty acyl carnitine, and liver triglycerides did not change with either treatment. PKC-θ activation during hyper-insulinemia decreased significantly following PPAR-α treatment.PPAR-α agonist treatment increases palmitate oxidation and decreases PKC activity along with reduced insulin sensitivity in acute trauma, However, a direct link between these responses cannot be attributed to alterations in intracellular lipid concentrations.Significant alterations in both glucose and fat metabolism occur following burn trauma. Hyperglycemia, due to increased hepatic gluconeogenesis and peripheral insulin resistance, is common [1]. Free fatty acid (FFA) cycling is increased up to three fold, and triglyceride (TAG) deposition in the liver is common [2]. Studies in burned animals indicate that mitochondrial number and oxidative capacity are severely reduced following burn, but how these changes relate to in vivo fatty acid oxidation is unclear [3]. Further, the relation between fat metabolism and insulin sensitivity is not well understood in the severely burned population.Decreased β-oxidation of FFA's and increased circula
Pulmonary vascular permeability changes in an ovine model of methicillin-resistant Staphylococcus aureus sepsis
Collette C Jonkam, Kamna Bansal, Daniel L Traber, Atsumori Hamahata, Marc O Maybauer, Dirk M Maybauer, Robert A Cox, Matthias Lange, Rhykka L Connelly, Lillian D Traber, Clarisse D Djukom, John R Salsbury, David N Herndon, Perenlei Enkhbaatar
Critical Care , 2009, DOI: 10.1186/cc7720
Abstract: Ewes were chronically instrumented, and randomised into either a control or MRSA sepsis (MRSA and smoke inhalation) group.Pulmonary function remained stable in the control group, whereas the MRSA sepsis group developed impaired gas exchange and significantly increased lung lymph flow, permeability index and bloodless wet-to-dry weight-ratio (W/D ratio). The plasma nitrate/nitrite (NOx) levels, lung inducible nitric oxide synthases (iNOS) and endothelial nitric oxide synthases (eNOS), vascular endothelial growth factor (VEGF) protein expressions and poly-(ADP)-ribose (PAR) were significantly increased by MRSA challenge.These results provide evidence that excessive NO production may mediate pulmonary vascular hyperpermeability in MRSA sepsis via up regulation of reactive radicals and VEGF.Despite advancements in the treatment of sepsis, its sequelae remain associated with increased risk of death among patients in intensive care units (ICU) [1]. From 1979 to 2000, the incidence of sepsis in the USA increased by 13.7%, and the number of sepsis-related in-hospital deaths rose from 43,579 in 1979 to 120,491 in 2000, with Gram-positive bacteria being increasingly recognised as the most common pathogens (52.1% versus 37.6% Gram negative) [2]. Pneumonia is one of the dominant causes of sepsis. Smoke inhalation injury is frequently complicated by pneumonia [3,4]. The mortality in fire victims increases by a maximum of 20% when associated with smoke inhalation injury alone, by 40% with pneumonia alone, but concomitantly they increase the mortality by up to 60% [4].Methicillin-resistant Staphylococcus aureus (MRSA) is one of the leading causes of nosocomial infections in burn patients [5]. Wang and colleagues [6] reported an increased number of patients with community-acquired MRSA bacteraemia and showed a close association with necrotizing pneumonia. Staphylococcus aureus has been reported to be a predominant cause (38%) of ventilator-associated pneumonia (VAP) in surgical ICU
Tissue engineered fetal skin constructs for pediatric burns
William B Norbury, Marc G Jeschke, David N Herndon
Critical Care , 2005, DOI: 10.1186/cc3881
Abstract: Partial thickness (second degree) burns involve all of the epidermis and some of the underlying dermis. Management and subsequent recovery depend on the amount of viable dermis remaining. A superficial partial thickness burn down to the papillary dermis will produce blistering, a painful pink wound bed with good capillary refill, and should heal with minimal amounts of hypertrophic scar formation in about 14–21 days. A deep partial thickness burn down to the reticular dermis will also produce blistering, but the wound bed may be paler and less painful, and there will be reduced or absent capillary refill. The wound will take longer than 21 days to heal, and the resulting scarring is likely to be poor, with significant wound contraction [1]. In the clinical setting the patient is unlikely to present with a wound that matches either of these descriptions, and so a thorough examination, together with use of laser Doppler, will help in the initial assessment of each wound. Considerable experience is needed to arrive at a clinical management decision.As outlined above, the initial management involves clean debridement of the blistered areas and thorough examination of the wound bed, along with laser Doppler imagery. Closing the wound quickly will help to reduce painful stimuli to the patient. Superficial partial thickness burns usually only require nonadherent dressings such as Mepitel? (M?lnlycke Health Care, Newtown, PA, USA); mid-partial thickness burns require the use of dressings or occasionally skin substitutes such as Biobrane? (Bertek Pharmaceuticals Inc, Morgantown, West Virginia, USA) or TransCyte? (Advanced Tissue Sciences, La Jolla, CA, USA).Mepitel? is a porous, semitransparent, low-adherence wound contact layer that consists of a flexible polyamide net coated with soft silicone. The silicone coating is slightly tacky, which facilitates the application and retention of the dressing to the peri-wound area. The dressing is placed directly onto the wound and se
Inhalation injury in severely burned children does not augment the systemic inflammatory response
Celeste C Finnerty, David N Herndon, Marc G Jeschke
Critical Care , 2007, DOI: 10.1186/cc5698
Abstract: Thirty severely burned pediatric patients with inhalation injury and 42 severely burned children without inhalation injury were enrolled in the study. Inhalation injury was diagnosed by bronchoscopy during the first operation. Blood was collected within 24 hours of admission and again at five to seven days following admission. Cytokine expression was profiled using multi-plex antibody-coated beads. Significance was accepted at a p value of less than 0.05.The mean percentages of total body surface area burned were 67% ± 4% (56% ± 6%, third-degree burns) in the inhalation injury group and 60% ± 3% (45% ± 3%, third-degree burns) in the non-inhalation injury group (p value not significant [NS]). Mean age was 9 ± 1 years in the inhalation injury group and 8 ± 1 years in the non-inhalation injury group (p value NS). Time from burn to admission in the inhalation injury group was 2 ± 1 days compared to 3 ± 1 days in the non-inhalation injury group (p value NS). Mortalities were 40% in the inhalation injury group and 12% in the non-inhalation injury group (p < 0.05). At the time of admission, serum interleukin (IL)-7 was significantly increased in the non-inhalation injury group, whereas IL-12p70 was significantly increased in the inhalation injury group compared to the non-inhalation injury group (p < 0.05). There were no other significant differences between groups. Five to seven days following admission, all cytokines decreased with no differences between the inhalation injury and non-inhalation injury cohorts.In the present study, we show that an inhalation injury causes alterations in IL-7 and IL-12p70. There were no increased levels of pro-inflammatory cytokines, indicating that an inhalation injury in addition to a burn injury does not augment the systemic inflammatory response early after burn.During the past 20 years, mortality from major burns has decreased due to improved intensive care unit care, improvements in wound management, better control of sepsis, and con
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