@article{conley_brown_westerman_elfenbein_sheats_2024, title={MARCKS Inhibition Alters Bovine Neutrophil Responses to <i>Salmonella</i> Typhimurium}, volume={12}, ISSN={["2227-9059"]}, url={https://www.mdpi.com/2227-9059/12/2/442}, DOI={10.3390/biomedicines12020442}, abstractNote={Neutrophils are innate immune cells that respond quickly to sites of bacterial infection and play an essential role in host defense. Interestingly, some bacterial pathogens benefit from exuberant neutrophil inflammation. Salmonella is one such pathogen that can utilize the toxic mediators released by neutrophils to colonize the intestine and cause enterocolitis. Because neutrophils can aid gut colonization during Salmonella infection, neutrophils represent a potential host-directed therapeutic target. Myristoylated alanine-rich C-kinase substrate (MARCKS) is an actin-binding protein that plays an essential role in many neutrophil effector responses. We hypothesized that inhibition of MARCKS protein would alter bovine neutrophil responses to Salmonella Typhimurium (STm) ex vivo. We used a MARCKS inhibitor peptide to investigate the role of MARCKS in neutrophil responses to STm. This study demonstrates that MARCKS inhibition attenuated STm-induced neutrophil adhesion and chemotaxis. Interestingly, MARCKS inhibition also enhanced neutrophil phagocytosis and respiratory burst in response to STm. This is the first report describing the role of MARCKS protein in neutrophil antibacterial responses.}, number={2}, journal={BIOMEDICINES}, author={Conley, Haleigh E. and Brown, Chalise F. and Westerman, Trina L. and Elfenbein, Johanna R. and Sheats, M. Katie}, year={2024}, month={Feb} }
 @article{klein_predeus_greissl_clark-herrera_cruz_cundiff_haeberle_howell_lele_robinson_et al._2024, title={Pathogenic diversification of the gut commensal <i>Providencia alcalifaciens</i> via acquisition of a second type III secretion system}, ISSN={["1098-5522"]}, DOI={10.1128/iai.00314-24}, abstractNote={ABSTRACT Providencia alcalifaciens is a Gram-negative bacterium found in various water and land environments and organisms, including insects and mammals. Some P. alcalifaciens strains encode gene homologs of virulence factors found in pathogenic Enterobacterales members, such as Salmonella enterica serovar Typhimurium and Shigella flexneri . Whether these genes are pathogenic determinants in P. alcalifaciens is not known. In this study, we investigated P. alcalifaciens –host interactions at the cellular level, focusing on the role of two type III secretion systems (T3SS) belonging to the Inv-Mxi/Spa family. T3SS 1b is widespread in Providencia spp. and encoded on the chromosome. A large plasmid that is present in a subset of P. alcalifaciens strains, primarily isolated from diarrheal patients, encodes for T3SS 1a . We show that P. alcalifaciens 205/92 is internalized into eukaryotic cells, lyses its internalization vacuole, and proliferates in the cytosol. This triggers caspase-4-dependent inflammasome responses in gut epithelial cells. The requirement for the T3SS 1a in entry, vacuole lysis, and cytosolic proliferation is host cell type-specific, playing a more prominent role in intestinal epithelial cells than in macrophages or insect cells. In a bovine ligated intestinal loop model, P. alcalifaciens colonizes the intestinal mucosa and induces mild epithelial damage with negligible fluid accumulation in a T3SS 1a - and T3SS 1b -independent manner. However, T3SS 1b was required for the rapid killing of Drosophila melanogaster . We propose that the acquisition of two T3SS has allowed P. alcalifaciens to diversify its host range, from a highly virulent pathogen of insects to an opportunistic gastrointestinal pathogen of animals.}, journal={INFECTION AND IMMUNITY}, author={Klein, Jessica A. and Predeus, Alexander V. and Greissl, Aimee R. and Clark-Herrera, Mattie M. and Cruz, Eddy and Cundiff, Jennifer A. and Haeberle, Amanda L. and Howell, Maya and Lele, Aaditi and Robinson, Donna J. and et al.}, year={2024}, month={Sep} }
 @article{cruz_haeberle_westerman_durham_suyemoto_knodler_elfenbein_2023, title={Nonredundant Dimethyl Sulfoxide Reductases Influence Salmonella enterica Serotype Typhimurium Anaerobic Growth and Virulence}, ISSN={["1098-5522"]}, DOI={10.1128/iai.00578-22}, abstractNote={Facultative anaerobic enteric pathogens can utilize a diverse array of alternate electron acceptors to support anaerobic metabolism and thrive in the hypoxic conditions within the mammalian gut. Dimethyl sulfoxide (DMSO) is produced by methionine catabolism and can act as an alternate electron acceptor to support anaerobic respiration.}, journal={INFECTION AND IMMUNITY}, author={Cruz, E. and Haeberle, A. L. and Westerman, T. L. and Durham, M. E. and Suyemoto, M. M. and Knodler, L. A. and Elfenbein, J. R.}, year={2023}, month={Feb} }
 @article{westerman_sheats_elfenbein_2021, title={Sulfate Import in Salmonella Typhimurium Impacts Bacterial Aggregation and the Respiratory Burst in Human Neutrophils}, volume={89}, ISSN={["1098-5522"]}, DOI={10.1128/IAI.00701-20}, abstractNote={During enteric salmonellosis, neutrophil-generated reactive oxygen species alter the gut microenvironment, favoring survival ofSalmonellaTyphimurium. While type 3 secretion system 1 (T3SS-1) and flagellar motility are potentSalmonellaTyphimurium agonists of the neutrophil respiratory burstin vitro,neither of these pathways alone is responsible for stimulation of a maximal respiratory burst.}, number={6}, journal={INFECTION AND IMMUNITY}, author={Westerman, T. L. and Sheats, M. K. and Elfenbein, J. R.}, year={2021}, month={Jun} }
 @article{westerman_mcclelland_elfenbein_2021, title={YeiE Regulates Motility and Gut Colonization in Salmonella enterica Serotype Typhimurium}, volume={12}, ISSN={["2150-7511"]}, DOI={10.1128/mBio.03680-20}, abstractNote={The ability to finely tune virulence factor gene expression is required for bacterial pathogens to successfully colonize a host. Flagellum-mediated motility is critical for many gut pathogens to establish productive infections.}, number={3}, journal={MBIO}, author={Westerman, T. L. and McClelland, M. and Elfenbein, J. R.}, year={2021} }
 @article{watson_hazen_rasko_jacob_elfenbein_stauffer_gookin_2021, title={Comparative Genomics of Atypical Enteropathogenic Escherichia coli from Kittens and Children Identifies Bacterial Factors Associated with Virulence in Kittens}, volume={89}, ISSN={["1098-5522"]}, DOI={10.1128/IAI.00619-20}, abstractNote={
            Typical enteropathogenic
            Escherichia coli
            (tEPEC) is a leading cause of diarrhea and associated death in children worldwide. Atypical EPEC (aEPEC) lacks the plasmid encoding bundle-forming pili and is considered less virulent, but the molecular mechanism of virulence is poorly understood.
          }, number={3}, journal={INFECTION AND IMMUNITY}, author={Watson, Victoria E. and Hazen, Tracy H. and Rasko, David A. and Jacob, Megan E. and Elfenbein, Johanna R. and Stauffer, Stephen H. and Gookin, Jody L.}, year={2021}, month={Mar} }
 @article{griewisch_pierce_elfenbein_2020, title={Genetic Determinants of Salmonella Resistance to the Biofilm-Inhibitory Effects of a Synthetic 4-Oxazolidinone Analog}, volume={86}, ISSN={0099-2240 1098-5336}, url={http://dx.doi.org/10.1128/aem.01120-20}, DOI={10.1128/AEM.01120-20}, abstractNote={
            Biofilms are resistant to killing by disinfectants and antimicrobials.
            S. enterica
            biofilms facilitate long-term host colonization and persistence in food processing environments. Synthetic analogs of 4-oxazolidinone natural products show promise as antibiofilm agents. Here, we show that a synthetic 4-oxazolidinone analog inhibits
            Salmonella
            biofilm through effects on both motility and biofilm matrix gene expression. Furthermore, we identify three genes that promote
            Salmonella
            resistance to the antibiofilm effects of the compound. This work provides insight into the mechanism of antibiofilm effects of a synthetic 4-oxazolidinone analog in Gram-negative bacteria and demonstrates new mechanisms of intrinsic antimicrobial resistance in
            Salmonella
            biofilms.
          }, number={20}, journal={Applied and Environmental Microbiology}, publisher={American Society for Microbiology}, author={Griewisch, K. F. and Pierce, J. G. and Elfenbein, J. R.}, editor={Kivisaar, MaiaEditor}, year={2020}, month={Aug} }
 @article{bogomolnaya_tilvawala_elfenbein_cirillo_andrews-polymenis_2020, title={Linearized Siderophore Products Secreted via MacAB Efflux Pump Protect Salmonella enterica Serovar Typhimurium from Oxidative Stress}, volume={11}, ISSN={["2150-7511"]}, DOI={10.1128/mBio.00528-20}, abstractNote={
            Nontyphoidal
            Salmonella
            bacteria induce a classic inflammatory diarrhea by eliciting a large influx of neutrophils, producing a robust oxidative burst. Despite substantial progress understanding the benefits to the host of the inflammatory response to
            Salmonella
            , little is known regarding how
            Salmonella
            can simultaneously resist the damaging effects of the oxidative burst. The multidrug efflux pump
            MacAB
            is important for survival of oxidative stress both
            in vitro
            and during infection. We describe a new pathway used by
            Salmonella
            Typhimurium to detoxify extracellular reactive oxygen species using a multidrug efflux pump (MacAB) to secrete a linear siderophore, a metabolite of enterobactin. The natural substrates of many multidrug efflux pumps are unknown, and functional roles of the linear metabolites of enterobactin are unknown. We bring two novel discoveries together to highlight an important mechanism used by
            Salmonella
            to survive under the oxidative stress conditions that this organism encounters during the classic inflammatory diarrhea that it also induces.
          }, number={3}, journal={MBIO}, author={Bogomolnaya, L. M. and Tilvawala, R. and Elfenbein, J. R. and Cirillo, J. D. and Andrews-Polymenis, H. L.}, year={2020} }
 @article{manship_blikslager_elfenbein_2019, title={Disease features of equine coronavirus and enteric salmonellosis are similar in horses}, volume={33}, ISSN={0891-6640 1939-1676}, url={http://dx.doi.org/10.1111/jvim.15386}, DOI={10.1111/jvim.15386}, abstractNote={BackgroundEquine coronavirus (ECoV) is an emerging pathogen associated with fever and enteric disease in adult horses. Clinical features of ECoV infection have been described, but no study has compared these features to those of Salmonella infections.ObjectivesCompare the clinical features of ECoV infection with enteric salmonellosis and establish a disease signature to increase clinical suspicion of ECoV infection in adult horses.AnimalsForty‐three horses >1 year of age with results of CBC, serum biochemistry, and fecal diagnostic testing for ECoV and Salmonella spp.MethodsMedical records of horses presented to the North Carolina State University Equine and Farm Animal Veterinary Center (2003‐016) were retrospectively reviewed. Horses were divided into 3 groups based on fecal diagnostic test results: ECoV‐positive, Salmonella‐positive, or unknown diagnosis (UNK). Time of year presented, clinical signs, CBC, and serum biochemistry test results were recorded. Data were analyzed by 1‐way analysis of variance, Kruskal‐Wallis test, or Fisher's exact test with significance set at P < .05.ResultsMost common presenting complaints were fever and colic and were similar across groups. Horses with ECoV had significantly decreased neutrophil counts when compared to those with no diagnosis but were not different from horses with Salmonella. Horses with Salmonella had significantly lower mean leukocyte counts compared to those with UNK. No significant differences were found among groups for any other examined variable.Conclusions and Clinical ImportanceEquine coronavirus and Salmonella infections share clinical features, suggesting both diseases should be differential diagnoses for horses with fever and enteric clinical signs.}, number={2}, journal={Journal of Veterinary Internal Medicine}, publisher={Wiley}, author={Manship, Arlie J. and Blikslager, Anthony T. and Elfenbein, Johanna R.}, year={2019}, month={Jan}, pages={912–917} }
 @article{durham_elfenbein_2019, title={Evaluation of vaporized hydrogen peroxide sterilization on the in vitro efficacy of meropenem-impregnated polymethyl methacrylate beads}, volume={80}, ISSN={["1943-5681"]}, DOI={10.2460/ajvr.80.1.45}, abstractNote={Abstract
OBJECTIVE To evaluate the effects of vaporized hydrogen peroxide (VHP) sterilization on the in vitro antimicrobial efficacy of meropenem-impregnated polymethyl methacrylate (M-PMMA) beads.
SAMPLE 6-mm-diameter polymethyl methacrylate beads that were or were not impregnated with meropenem.
PROCEDURES Meropenem-free polymethyl methacrylate and M-PMMA beads were sterilized by use of an autoclave or VHP or remained unsterilized. To determine the antimicrobial efficacy of each bead-sterilization combination (treatment), Mueller-Hinton agar plates were inoculated with 1 of 6 common equine pathogens, and 1 bead from each treatment was applied to a sixth of each plate. The zone of bacterial inhibition for each treatment was measured after 24 hours. To estimate the duration of antimicrobial elution into a solid or liquid medium, 1 bead from each treatment was transferred every 24 hours to a new Staphylococcus aureus–inoculated agar plate or a tube with PBS solution, and an aliquot of the eluent from each tube was then applied to a paper disc on an S aureus–inoculated agar plate. All agar plates were incubated for 24 hours, and the zone of bacterial inhibition was measured for each treatment.
RESULTS In vitro antimicrobial efficacy of M-PMMA beads was retained following VHP sterilization. The duration of antimicrobial elution in solid and liquid media did not differ significantly between unsterilized and VHP-sterilized M-PMMA beads.
CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that M-PMMA beads retained in vitro antimicrobial activity and eluted the drug for up to 2 weeks after VHP sterilization.}, number={1}, journal={AMERICAN JOURNAL OF VETERINARY RESEARCH}, author={Durham, Myra E. and Elfenbein, Johanna R.}, year={2019}, month={Jan}, pages={45–50} }
 @article{knodler_elfenbein_2019, title={Salmonella enterica}, volume={27}, ISSN={["1878-4380"]}, DOI={10.1016/j.tim.2019.05.002}, abstractNote={Salmonella enterica is a zoonotic pathogen of substantial concern to global human and animal health. It is a leading cause of morbidity and mortality in people worldwide. S. enterica can successfully colonize animals, humans, and plants, and is also found in the environment. Some serovars have a broad host range (S. Typhimurium and S. Enteriditis), others are host-adapted (S. Typhi and S. Paratyphi A and C). Following ingestion, S. enterica invades the intestinal epithelium in the ileum and colon, either to cause a neutrophilic gastroenteritis or disseminate to systemic sites and cause sepsis.}, number={11}, journal={TRENDS IN MICROBIOLOGY}, author={Knodler, Leigh A. and Elfenbein, Johanna R.}, year={2019}, month={Nov}, pages={964–965} }
 @article{jaslow_gibbs_fricke_wang_pittman_mammel_thaden_fowler_hammer_elfenbein_et al._2018, title={Salmonella Activation of STAT3 Signaling by SarA Effector Promotes Intracellular Replication and Production of IL-10}, volume={23}, ISSN={["2211-1247"]}, DOI={10.1016/j.celrep.2018.05.072}, abstractNote={Salmonella enterica is an important foodborne pathogen that uses secreted effector proteins to manipulate host pathways to facilitate survival and dissemination. Different S. enterica serovars cause disease syndromes ranging from gastroenteritis to typhoid fever and vary in their effector repertoire. We leveraged this natural diversity to identify stm2585, here designated sarA (Salmonella anti-inflammatory response activator), as a Salmonella effector that induces production of the anti-inflammatory cytokine IL-10. RNA-seq of cells infected with either ΔsarA or wild-type S. Typhimurium revealed that SarA activates STAT3 transcriptional targets. Consistent with this, SarA is necessary and sufficient for STAT3 phosphorylation, STAT3 inhibition blocks IL-10 production, and SarA and STAT3 interact by co-immunoprecipitation. These effects of SarA contribute to intracellular replication in vitro and bacterial load at systemic sites in mice. Our results demonstrate the power of using comparative genomics for identifying effectors and that Salmonella has evolved mechanisms for activating an important anti-inflammatory pathway.}, number={12}, journal={CELL REPORTS}, author={Jaslow, Sarah L. and Gibbs, Kyle D. and Fricke, W. Florian and Wang, Liuyang and Pittman, Kelly J. and Mammel, Mark K. and Thaden, Joshua T. and Fowler, Vance G., Jr. and Hammer, Gianna E. and Elfenbein, Johanna R. and et al.}, year={2018}, month={Jun}, pages={3525–3536} }
 @article{westerman_bogomolnaya_andrews-polymenis_sheats_elfenbein_2018, title={The Salmonella type-3 secretion system-1 and flagellar motility influence the neutrophil respiratory burst}, volume={13}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0203698}, abstractNote={Neutrophils are innate immune response cells designed to kill invading microorganisms. One of the mechanisms neutrophils use to kill bacteria is generation of damaging reactive oxygen species (ROS) via the respiratory burst. However, during enteric salmonellosis, neutrophil-derived ROS actually facilitates Salmonella expansion and survival in the gut. This seeming paradox led us to hypothesize that Salmonella may possess mechanisms to influence the neutrophil respiratory burst. In this work, we used an in vitro Salmonella-neutrophil co-culture model to examine the impact of enteric infection relevant virulence factors on the respiratory burst of human neutrophils. We report that neutrophils primed with granulocyte-macrophage colony stimulating factor and suspended in serum containing complement produce a robust respiratory burst when stimulated with viable STm. The magnitude of the respiratory burst increases when STm are grown under conditions to induce the expression of the type-3 secretion system-1. STm mutants lacking the type-3 secretion system-1 induce less neutrophil ROS than the virulent WT. In addition, we demonstrate that flagellar motility is a significant agonist of the neutrophil respiratory burst. Together our data demonstrate that both the type-3 secretion system-1 and flagellar motility, which are established virulence factors in enteric salmonellosis, also appear to directly influence the magnitude of the neutrophil respiratory burst in response to STm in vitro.}, number={9}, journal={PLOS ONE}, author={Westerman, Trina L. and Bogomolnaya, Lydia and Andrews-Polymenis, Helene L. and Sheats, M. Katherine and Elfenbein, Johanna R.}, year={2018}, month={Sep} }
 @article{yang_bogomolnaya_elfenbein_endicott-yazdani_reynolds_porwollik_cheng_xia_mcclelland_andrews-polymenis_2016, title={Novel Two-Step Hierarchical Screening of Mutant Pools Reveals Mutants under Selection in Chicks}, volume={84}, ISSN={["1098-5522"]}, DOI={10.1128/iai.01525-15}, abstractNote={ABSTRACT
          
            Contaminated chicken/egg products are major sources of human salmonellosis, yet the strategies used by
            Salmonella
            to colonize chickens are poorly understood. We applied a novel two-step hierarchical procedure to identify new genes important for colonization and persistence of
            Salmonella enterica
            serotype Typhimurium in chickens. A library of 182
            S.
            Typhimurium mutants each containing a targeted deletion of a group of contiguous genes (for a total of 2,069 genes deleted) was used to identify regions under selection at 1, 3, and 9 days postinfection in chicks. Mutants in 11 regions were under selection at all assayed times (colonization mutants), and mutants in 15 regions were under selection only at day 9 (persistence mutants). We assembled a pool of 92 mutants, each deleted for a single gene, representing nearly all genes in nine regions under selection. Twelve single gene deletion mutants were under selection in this assay, and we confirmed 6 of 9 of these candidate mutants via competitive infections and complementation analysis in chicks.
            STM0580
            ,
            STM1295
            ,
            STM1297
            ,
            STM3612
            ,
            STM3615
            , and
            STM3734
            are needed for
            Salmonella
            to colonize and persist in chicks and were not previously associated with this ability. One of these key genes,
            STM1297
            (
            selD
            ), is required for anaerobic growth and supports the ability to utilize formate under these conditions, suggesting that metabolism of formate is important during infection. We report a hierarchical screening strategy to interrogate large portions of the genome during infection of animals using pools of mutants of low complexity. Using this strategy, we identified six genes not previously known to be needed during infection in chicks, and one of these (
            STM1297
            ) suggests an important role for formate metabolism during infection.
          }, number={4}, journal={INFECTION AND IMMUNITY}, author={Yang, Hee-Jeong and Bogomolnaya, Lydia M. and Elfenbein, Johanna R. and Endicott-Yazdani, Tiana and Reynolds, M. Megan and Porwollik, Steffen and Cheng, Pui and Xia, Xiao-Qin and McClelland, Michael and Andrews-Polymenis, Helene}, year={2016}, month={Apr}, pages={1226–1238} }
 @article{elfenbein_knodler_nakayasu_ansong_brewer_bogomolnaya_adams_mcclelland_adkins_andrews-polymenis_2015, title={Multicopy single-stranded DNA directs intestinal colonization of enteric pathogens}, volume={11}, number={9}, journal={PLoS Genetics}, author={Elfenbein, J. R. and Knodler, L. A. and Nakayasu, E. S. and Ansong, C. and Brewer, H. M. and Bogomolnaya, L. and Adams, L. G. and McClelland, M. and Adkins, J. N. and Andrews-Polymenis, H. L.}, year={2015} }
 @article{elfenbein_robertson_mackay_kukanich_sanchez_2014, title={Systemic and anti-nociceptive effects of prolonged lidocaine, ketamine, and butorphanol infusions alone and in combination in healthy horses}, volume={10}, ISSN={1746-6148}, url={http://dx.doi.org/10.1186/1746-6148-10-S1-S6}, DOI={10.1186/1746-6148-10-S1-S6}, abstractNote={Prolonged drug infusions are used to treat horses with severe signs of pain, but can be associated with altered gastrointestinal transit. The purpose of this study was to determine the effects of prolonged constant rate infusions (CRI) of lidocaine (L), butorphanol (B), and ketamine (K) alone and in combination on gastrointestinal transit, behavior, and thermal nociceptive threshold in healthy horses.Eight healthy adult horses were used in a randomized, cross-over, blinded, prospective experimental trial. Interventions were saline, L, K, B, LK, LB, BK, and LBK as an intravenous CRI for 96 hours. Drugs were mixed or diluted in saline; following a bolus, CRI rate was 0.15 mL/kg/hr with drug doses as follows: L - 1.3 mg/kg then 3 mg/kg/hr; B - 0.018 mg/kg then 0.013 mg/kg/hr; K - 0.55 mg/kg then 0.5 mg/kg/hr. Two-hundred plastic beads were administered intragastrically by nasogastric tube immediately prior to the bolus. Feces were collected every 2 hours, weighed, and beads manually retrieved. Behavior was scored every 2 hours, vital parameters every 6 hours, and thermal nociceptive threshold every 12 hours for 96 hours. Drug concentrations in the LBK solution were tested every 6 hours for 72 hours.Four of 64 trials (3 LBK, 1 BK) were discontinued early due to signs of abdominal discomfort. There were no apparent differences between groups in vital parameters or thermal threshold. Transit time was delayed for LB and LBK with a corresponding decrease in fecal weight that was most severe in the final 24 hours of infusion. Significant changes in behavior scores, vital parameters, or thermal threshold were not observed. The concentration of each drug in the combined solution declined by less than 31% over the sampling period.Drug combinations containing butorphanol cause an apparent delay in gastrointestinal transit in healthy horses without substantially affecting somatic nociception at the doses studied. Combinations of lidocaine and ketamine may have less impact on gastrointestinal transit than infusions combined with butorphanol. Further work is needed to determine the effects of these drugs in painful or critically ill patients.}, number={Suppl 1}, journal={BMC Veterinary Research}, publisher={Springer Nature}, author={Elfenbein, Johanna R and Robertson, Sheilah A and MacKay, Robert J and KuKanich, Butch and Sanchez, L}, year={2014}, pages={S6} }
 @article{elfenbein_endicott-yazdani_porwollik_bogomolnaya_cheng_guo_zheng_yang_talamantes_shields_et al._2013, title={Novel Determinants of Intestinal Colonization of Salmonella enterica Serotype Typhimurium Identified in Bovine Enteric Infection}, volume={81}, ISSN={0019-9567 1098-5522}, url={http://dx.doi.org/10.1128/IAI.00874-13}, DOI={10.1128/IAI.00874-13}, abstractNote={ABSTRACT
          
            Cattle are naturally infected with
            Salmonella enterica
            serotype Typhimurium and exhibit pathological features of enteric salmonellosis that closely resemble those in humans. Cattle are the most relevant model of gastrointestinal disease resulting from nontyphoidal
            Salmonella
            infection in an animal with an intact microbiota. We utilized this model to screen a library of targeted single-gene deletion mutants to identify novel genes of
            Salmonella
            Typhimurium required for survival during enteric infection. Fifty-four candidate mutants were strongly selected, including numerous mutations in genes known to be important for gastrointestinal survival of salmonellae. Three genes with previously unproven phenotypes in gastrointestinal infection were tested in bovine ligated ileal loops. Two of these mutants,
            STM3602
            and
            STM3846
            , recapitulated the phenotype observed in the mutant pool. Complementation experiments successfully reversed the observed phenotypes, directly linking these genes to the colonization defects of the corresponding mutant strains.
            STM3602
            encodes a putative transcriptional regulator that may be involved in phosphonate utilization, and
            STM3846
            encodes a retron reverse transcriptase that produces a unique RNA-DNA hybrid molecule called multicopy single-stranded DNA. The genes identified in this study represent an exciting new class of virulence determinants for further mechanistic study to elucidate the strategies employed by
            Salmonella
            to survive within the small intestines of cattle.
          }, number={11}, journal={Infection and Immunity}, publisher={American Society for Microbiology}, author={Elfenbein, Johanna R. and Endicott-Yazdani, Tiana and Porwollik, Steffen and Bogomolnaya, Lydia M. and Cheng, Pui and Guo, Jinbai and Zheng, Yi and Yang, Hee-Jeong and Talamantes, Marissa and Shields, Christine and et al.}, editor={Fang, F. C.Editor}, year={2013}, month={Sep}, pages={4311–4320} }
 @article{mcgowan_elfenbein_robertson_sanchez_2012, title={Effect of butorphanol on thermal nociceptive threshold in healthy pony foals}, volume={45}, ISSN={0425-1644}, url={http://dx.doi.org/10.1111/j.2042-3306.2012.00673.x}, DOI={10.1111/j.2042-3306.2012.00673.x}, abstractNote={SummaryReasons for performing studyPain management is an important component of foal nursing care, and no objective data currently exist regarding the analgesic efficacy of opioids in foals.ObjectivesTo evaluate the somatic antinociceptive effects of 2 commonly used doses of intravenous (i.v.) butorphanol in healthy foals. Our hypothesis was that thermal nociceptive threshold would increase following i.v. butorphanol in a dose‐dependent manner in both neonatal and older pony foals.MethodsSeven healthy neonatal pony foals (age 1–2 weeks), and 11 healthy older pony foals (age 4–8 weeks). Five foals were used during both age periods. Treatments, which included saline (0.5 ml), butorphanol (0.05 mg/kg bwt) and butorphanol (0.1 mg/kg bwt), were administered i.v. in a randomised crossover design with at least 2 days between treatments. Response variables included thermal nociceptive threshold, skin temperature and behaviour score. Data within each age period were analysed using a 2‐way repeated measures ANOVA, followed by a Holm–Sidak multiple comparison procedure if warranted.ResultsThere was a significant (P<0.05) increase in thermal threshold, relative to Time 0, following butorphanol (0.1 mg/kg bwt) administration in both age groups. No significant time or treatment effects were apparent for skin temperature. Significant time, but not treatment, effects were evident for behaviour score in both age groups.ConclusionsButorphanol (0.1 mg/kg bwt, but not 0.05 mg/kg bwt) significantly increased thermal nociceptive threshold in neonatal and older foals without apparent adverse behavioural effects.Potential relevanceButorphanol shows analgesic potential in foals for management of somatic painful conditions.}, number={4}, journal={Equine Veterinary Journal}, publisher={Wiley}, author={McGowan, K. T. and Elfenbein, J. R. and Robertson, S. A. and Sanchez, L. C.}, year={2012}, month={Nov}, pages={503–506} }
 @article{elfenbein_sanchez_2012, title={Prevalence of gastric and duodenal ulceration in 691 nonsurviving foals (1995-2006)}, volume={44}, ISSN={0425-1644}, url={http://dx.doi.org/10.1111/j.2042-3306.2011.00449.x}, DOI={10.1111/j.2042-3306.2011.00449.x}, abstractNote={SummaryReason for performing study:Gastric ulcer disease is reported to be a significant cause of morbidity in foals, but the prevalence of ulcers in this population has not recently been evaluated.Objectives:To determine the prevalence of gastric and duodenal ulceration in nonsurviving foals, and the association of ulceration with the body system of primary diagnosis. Secondary objectives were to evaluate a potential association between age and ulcer prevalence and to evaluate the use of antacid medication in the neonatal hospital population during the study years.Methods:Necropsy records were searched for all equine accessions from 1995 to 2006. Foals aged from one day to 6 months were included. Year, age, breed, sex, diagnosis and the presence of glandular, nonglandular and/or duodenal ulceration were recorded. Diagnoses were divided into groups based on the body system of primary diagnosis, with multiple diagnoses possible. A computerised database was searched for antacid treatment of all neonatal admissions.Results:The overall prevalence of ulcers was 22%, with nonglandular ulcers predominating. Ulceration was significantly associated with gastrointestinal disease. There was no significant change in ulcer prevalence over time, although there was a significant decrease in the use of antacid medications in the later study years. Neonatal foals (<1 month) had a lower ulcer prevalence than older foals.Conclusions:The prevalence of ulcers in foals, although low, has remained stable over time. Gastric or duodenal ulcers are associated with a primary diagnosis of gastrointestinal disease and are less prevalent in neonates.Potential relevance:The prevalence of ulcers in nonsurviving foals is low. Foals with gastrointestinal disease are more likely to have ulcers than foals with other primary diagnoses, and older foals are more likely to have ulceration than neonates. The prevalence of ulceration did not appear to be related to hospital‐wide antacid medication use in neonates.}, journal={Equine Veterinary Journal}, publisher={Wiley}, author={Elfenbein, J. R. and Sanchez, L. C.}, year={2012}, month={Feb}, pages={76–79} }
 @article{ellis_hart_elfenbein_2011, title={Pathology in Practice}, volume={238}, ISSN={0003-1488}, url={http://dx.doi.org/10.2460/javma.238.11.1417}, DOI={10.2460/javma.238.11.1417}, abstractNote={A 4-month-old sexually intact male Miniature Horse was evaluated in October at the University of Georgia Veterinary Teaching Hospital because of anorexia of approximately 2 days' duration and dark brown, watery diarrhea (feces passed 2 or 3 times) and colic, both of < 24 hours' duration. Clinical and Gross FindingsAbnormalities detected at the initial physical examination on day 1 included depressed mentation, prolonged capillary refill time (3.5 seconds), dry mucous membranes consistent with 8% to 10% dehydration, borborygmi indicative of gastrointestinal tract hypermotility, and diarrhea (evidenced by fecal staining of the perineum).Clinicopathologic abnormalities included leukocytosis (neutrophilia with a left shift and lymphocytosis); severe hypoproteinemia and hypoalbuminemia; high serum creatinine concentration; hyponatremia, hypochloremia, hypocalcemia, and hyperlactatemia; and metabolic acidosis.Transabdominal ultrasonography revealed abnormally thick (7-to 18-mm) walls of the small intestine and large colon and fluid ingesta in the colon.Treatment included administration of flunixin meglumine, ethoxylated amylopectin, plasma, crystalloid fluids, doxycycline, metronidazole, and gastroprotectants.During the first few hours of hospitalization, the foal}, number={11}, journal={Journal of the American Veterinary Medical Association}, publisher={American Veterinary Medical Association (AVMA)}, author={Ellis, Angela E. and Hart, Kelsey A. and Elfenbein, Johanna R.}, year={2011}, month={Jun}, pages={1417–1419} }
 @article{elfenbein_robertson_corser_urion_sanchez_2011, title={Systemic Effects of a Prolonged Continuous Infusion of Ketamine in Healthy Horses}, volume={25}, ISSN={0891-6640}, url={http://dx.doi.org/10.1111/j.1939-1676.2011.0761.x}, DOI={10.1111/j.1939-1676.2011.0761.x}, abstractNote={Background:Ketamine as continuous rate infusion (CRI) provides analgesia in hospitalized horses.Objective:Determine effects of prolonged CRI of ketamine on gastrointestinal transit time, fecal weight, vital parameters, gastrointestinal borborygmi, and behavior scores in healthy adult horses.Animals:Seven adult Thoroughbred or Thoroughbred cross horses, with permanently implanted gastric cannulae.Methods:Nonblinded trial. Random assignment to 1 of 2 crossover designed treatments. Ketamine (0.55 mg/kg IV over 15 minutes followed by 1.2 mg/kg/h) or lactated Ringer's solution (50 mL IV over 15 minutes followed by 0.15 mL/kg/h) treatments. Two hundred 3 × 5 mm plastic beads administered by nasogastric tube before drug administration. Every 2 hours vital parameters, behavior scores recorded, feces collected and weighed, and beads retrieved. Every 6 hours gastrointestinal borborygmi scores recorded. Study terminated upon retrieval of 180 beads (minimum 34 hours) or maximum 96 hours. Nontransit time data analyzed between hours 0 and 34.Results:No significant (P< .05) differences detected between treatments in vital signs or gastrointestinal borborygmi. Significant (P= .002) increase in behavior score during ketamine infusion (0.381) from hours 24–34 compared with placebo (0). Ketamine caused significant delay in passage of 25, 50, and 75% of beads (ketamine = 30.6 ± 5.3, 41.4 ± 8.4, 65.3 ± 13.5 hours versus placebo = 26.8 ± 7.9, 34.3 ± 11.1, 45.8 ± 19.4 hours), and significant (P< .05) decrease in fecal weight from hours 22 (12.6 ± 3.2 versus 14.5 ± 3.8 kg) through 34 (18.5 ± 3.9 versus 12.8 ± 6.4 kg) of infusion.Conclusions and Clinical Importance:Ketamine CRI delayed gastrointestinal transit time in healthy horses without effect on vital parameters.}, number={5}, journal={Journal of Veterinary Internal Medicine}, publisher={Wiley}, author={Elfenbein, J.R. and Robertson, S.A. and Corser, A.A. and Urion, R.J. and Sanchez, L.C.}, year={2011}, month={Jul}, pages={1134–1137} }
 @article{elfenbein_giguère_meyer_javsicas_farina_zimmel_sanchez_2010, title={The Effects of Deferoxamine Mesylate on Iron Elimination after Blood Transfusion in Neonatal Foals}, volume={24}, ISSN={0891-6640}, url={http://dx.doi.org/10.1111/j.1939-1676.2010.0621.x}, DOI={10.1111/j.1939-1676.2010.0621.x}, abstractNote={BACKGROUND
Hepatic failure is one of the more common complications in foals requiring blood transfusion to treat neonatal isoerythrolysis. Iron intoxication is likely the cause of hepatic injury.


OBJECTIVES
To determine the effects of deferoxamine on iron elimination in normal foals.


ANIMALS
Thirteen neonatal foals.


METHODS
Randomized-controlled trial. At 1-3 days of age, foals received either 3 L of washed packed dam's red blood cells (RBC) or 3 L of saline IV once. Foals were treated with deferoxamine (1 g) or saline (5 mL) SC twice daily for 14 days. Foals were randomly assigned to 1 of 3 groups: RBC/deferoxamine (deferoxamine), RBC/saline (placebo), or saline/saline (control). Blood and urine samples and liver biopsy specimens were collected for measurement of hematological, biochemical, and iron metabolism variables.


RESULTS
There was a significant (P<.05) increase in hematocrit, RBC count, and hemoglobin in the groups transfused with packed RBC as compared with controls at all times. Biochemical variables and liver biopsy scores were not significantly different between groups at any time. Urine iron concentrations and fractional excretion of iron were significantly higher in deferoxamine treated foals. By 14 days after transfusion, liver iron concentrations in foals treated with deferoxamine (79.9±30.9 ppm) were significantly lower than that of foals receiving placebo (145±53.0 ppm) and similar to that of controls (44.8±4.09 ppm).


CONCLUSIONS AND CLINICAL IMPORTANCE
Deferoxamine enhances urinary iron elimination and decreases hepatic iron accumulation after blood transfusion in foals.}, number={6}, journal={Journal of Veterinary Internal Medicine}, publisher={Wiley}, author={Elfenbein, J.R. and Giguère, S. and Meyer, S.K. and Javsicas, L.H. and Farina, L.L. and Zimmel, D.N. and Sanchez, L.C.}, year={2010}, month={Oct}, pages={1475–1482} }
 @article{elfenbein_sanchez_robertson_cole_sams_2009, title={Effect of detomidine on visceral and somatic nociception and duodenal motility in conscious adult horses}, volume={36}, ISSN={1467-2987}, url={http://dx.doi.org/10.1111/j.1467-2995.2008.00441.x}, DOI={10.1111/j.1467-2995.2008.00441.x}, abstractNote={OBJECTIVE
To evaluate the effects of detomidine on visceral and somatic nociception, heart and respiratory rates, sedation, and duodenal motility and to correlate these effects with serum detomidine concentrations.


STUDY DESIGN
Nonrandomized, experimental trial.


ANIMALS
Five adult horses, each with a permanent gastric cannula weighing 534 +/- 46 kg.


METHODS
Visceral nociception was evaluated by colorectal (CRD) and duodenal distension (DD). The duodenal balloon was used to assess motility. Somatic nociception was assessed via thermal threshold (TT). Nose-to-ground (NTG) height was used as a measure of sedation. Serum was collected for pharmacokinetic analysis. Detomidine (10 or 20 microg kg(-1)) was administered intravenously. Data were analyzed by means of a three-factor anova with fixed factors of treatment and time and random factor of horse. When a significant time x treatment interaction was detected, differences were compared with a simple t-test or Bonferroni t-test. Significance was set at p < 0.05.


RESULTS
Detomidine produced a significant, dose-dependent decrease in NTG height, heart rate, and skin temperature and a significant, nondose-dependent decrease in respiratory rate. Colorectal distension threshold was significantly increased with 10 microg kg(-1) for 15 minutes and for at least 165 minutes with 20 microg kg(-1). Duodenal distension threshold was significantly increased at 15 minutes for the 20 microg kg(-1) dose. A significant change in TT was not observed at either dose. A marked, immediate decrease in amplitude of duodenal contractions followed detomidine administration at both doses for 50 minutes.


CONCLUSIONS AND CLINICAL RELEVANCE
Detomidine caused a longer period of visceral anti-nociception as determined by CRD but a shorter period of anti-nociception as determined by DD than has been previously reported. The lack of somatic anti-nociception as determined by TT testing may be related to the marked decrease in skin temperature, likely caused by peripheral vasoconstriction and the low temperature cut-off of the testing device.}, number={2}, journal={Veterinary Anaesthesia and Analgesia}, publisher={Elsevier BV}, author={Elfenbein, Johanna R and Sanchez, L Chris and Robertson, Sheilah A and Cole, Cynthia A and Sams, Richard}, year={2009}, month={Mar}, pages={162–172} }
 @article{kubiski_rech_camus_pellegrini-masini_elfenbein_howerth_2009, title={Pathology In Practice}, volume={235}, ISSN={0003-1488}, url={http://dx.doi.org/10.2460/javma.235.4.381}, DOI={10.2460/javma.235.4.381}, abstractNote={A 2-year-old Arabian filly had been imported to the United States from Germany as a weanling in the fall of 2006.In July 2007, the horse developed weight loss and respiratory tract signs including cough and nasal discharge.Treatment with trimethoprim-sulfamethoxazole resulted in clinical improvement for a short period, but in December 2007, the horse began to lose weight again and became lethargic and dyspneic.The horse was referred for evaluation in January 2008. Clinical and Gross FindingsAt the initial evaluation, the horse weighed 331.1 kg (728.4 lb) and was thin (body condition score, 2.5 on a scale of 1 to 9).Rectal temperature was 37.2°C (98.9°F), heart rate was 36 beats/min, and respiratory rate was 44 breaths/min.Mucopurulent nasal discharge from both nares was evident, and a productive cough was elicited via gentle tracheal palpation.Diffuse crackles and wheezes were detected via thoracic auscultation, and a tracheal rattle was noticeable via tracheal auscultation.Thoracic radiography revealed multiple moderately well-defined soft tissue opacities (ranging from 1-cm nodules to larger, coalescing masses [9 to 10 cm in diameter]), consistent}, number={4}, journal={Journal of the American Veterinary Medical Association}, publisher={American Veterinary Medical Association (AVMA)}, author={Kubiski, Steven V. and Rech, Raquel R. and Camus, Melinda S. and Pellegrini-Masini, Alessandra and Elfenbein, Johanna R. and Howerth, Elizabeth W.}, year={2009}, month={Aug}, pages={381–383} }
 @article{sanchez_elfenbein_robertson_2008, title={Effect of acepromazine, butorphanol, or N-butylscopolammonium bromide on visceral and somatic nociception and duodenal motility in conscious horses}, volume={69}, ISSN={0002-9645}, url={http://dx.doi.org/10.2460/ajvr.69.5.579}, DOI={10.2460/ajvr.69.5.579}, abstractNote={Abstract
Objective—To evaluate effects of butorphanol, acepromazine, and N-butylscopolammonium bromide (NBB) on visceral and somatic nociception and duodenal motility in conscious, healthy horses.
Animals—6 adult horses.
Procedures—Visceral nociception was evaluated by use of colorectal distention (CRD) and duodenal distention (DD) threshold. Somatic nociception was evaluated via thermal threshold (TT). Nose-to-ground height, heart rate, and respiratory rate were also measured. Each horse received each treatment in randomized order; investigators were not aware of treatments. Butorphanol was administered IV as a bolus (18 μg/kg) followed by constant rate infusion at 13 μg/kg/h for 2 hours, whereas acepromazine (0.04 mg/kg), NBB (0.3 mg/kg), and saline (0.9% NaCl) solution (2 mL) were administered IV as a bolus followed by constant rate infusion with saline solution (10 mL/h) for 2 hours. Variables were measured before and for 3 hours after treatment. Data were analyzed by use of a 3-factor ANOVA followed by a Bonferroni t test for multiple comparisons.
Results—Nose-to-ground height decreased after acepromazine. Respiratory rate decreased after acepromazine and increased after butorphanol. Heart rate increased briefly after NBB. Some horses had an increase in TT after butorphanol and acepromazine, but there was not a significant treatment effect over time. Drug effect on DD or motility was not evident. The CRD threshold increased significantly at 5, 65, 155, and 185 minutes after acepromazine and from 5 to 65 minutes after NBB.
Conclusions and Clinical Relevance—Each drug caused predictable changes in sedation and vital signs, but consistent anti-nociceptive effects were not evident.}, number={5}, journal={American Journal of Veterinary Research}, publisher={American Veterinary Medical Association (AVMA)}, author={Sanchez, L. Chris and Elfenbein, Johanna R. and Robertson, Sheilah A.}, year={2008}, month={May}, pages={579–585} }
 @article{elfenbein_credille_camus_leroy_blas-machado_woolums_2008, title={Hypoglycemia and Hyperlactatemia Associated with Lymphoma in an Angus Cow}, volume={22}, ISSN={0891-6640 1939-1676}, url={http://dx.doi.org/10.1111/j.1939-1676.2008.0184.x}, DOI={10.1111/j.1939-1676.2008.0184.x}, abstractNote={A 7-year-old Angus cow was examined for fever and apparent respiratory disease of 2 weeks duration that was nonresponsive to administration of antimicrobials. The cow was purchased from a commercial Angus breeder 6 months before examination and was housed on pasture with 60 other adult cows and 30 calves. Approximately 2 weeks before the cow's examination, 9 of the 30 calves and 1 other adult cow developed clinical signs of respiratory disease. At that time, each calf and affected adult cows were treated with florfenicola (20 mg/kg IM once). All other treated animals improved with antimicrobial therapy. Owing to poor initial response to therapy, the owner treated the cow that was subsequently referred for evaluation with a second 20 mg/kg dose of florfenicol and 2 additional doses of 40 mg/kg IM at 3-day interval. Over the 2-week interval before examination, the cow lost body condition despite a good appetite. On examination, the cow was quiet, alert, and responsive and had a body condition score of 3/9. The cow was febrile (rectal temperature 106.3°F) and tachypneic (respiratory rate 96 breaths/min [bpm]) with a normal heart rate (80 bpm). Vulvar mucous membranes were pink and moist with a capillary refill time of 2 seconds. No cardiac murmurs or arrhythmias were noted on thoracic auscultation. Increased breath sounds were noted in all lung fields. There was no nasal discharge. Size of prescapular and prefemoral lymph nodes was within normal limits. Rumenal contractions were decreased and mucoid discharge was present from the rectum consistent with decreased fecal production. Transrectal palpation revealed a gravid uterus with a 4-month-old fetus. Initial laboratory testing revealed anemia (PCV 21.5%; reference range, 24–46%) and hypoproteinemia (total solids 6.5 g/dL; reference range, 6.7–7.5 g/dL). The buffy coat layer within the microhematocrit tube was prominent. Serum biochemical analysis revealed hypoproteinemia (total protein, 6.2 g/dL; reference range, 6.8–7.6 g/dL), hypoglycemia (glucose, 5 mg/dL; reference range, 44–102 mg/dL), hyperkalemia (potassium, 5.8 mmol/L; reference range, 3.6–4.7 mmol/L), hypochloremia (chloride, 91 mmol/L; reference range, 98–109 mmol/L), high anion gap metabolic acidosis (bicarbonate, 11 mmol/L; reference range, 22–31 mmol/L; anion gap, 45 mmol/L; reference range, 16–23 mmol/L), and elevated activity of γ-glutamyltransferase (GGT, 71 U/L; reference range,1 15–39 U/L), and sorbitol dehydrogenase (SDH, 120.6 U/L; reference range,1 12–53 U/L). There was hyposthenuria (urine specific gravity [USG], 1.002) and aciduria (pH 5.0) with no glucose or ketones. Blood pH was 7.45 (reference range, 7.35–7.45) with a decreased plasma bicarbonate concentration (bicarbonate, 10.3 mmol/L; reference range, 22–31 mmol/L), hyperlactatemia (lactate, 17.7 mmol/L; reference range, 0.56–2.22 mmol/L), hypocapnia (PaCO2, 14.9 mmHg; reference range, 35–44 mmHg), hypoxemia (PaO2, 84.9 mmHg; reference range, > 85 mmHg), and a low base excess (− 14.0 mmol/L; reference range, 4–6 mmol/L). These findings were interpreted to represent a mixed titration-type metabolic acidosis and respiratory alkalosis, with the metabolic acidosis owing to hyperlactatemia, and the respiratory alkalosis owing to hyperventilation associated with tachypnea caused by severe hyperthermia. It was also possible that the blood gas results represented respiratory compensation for metabolic acidosis, but because in most cases compensation does not bring the blood pH into the normal range, a mixed disorder was considered more likely. In order to confirm the profound hypoglycemia and rule-out the possibility of preanalytical consumption of glucose by the leukocytes, the cow's blood glucose was also measured with a patient-side glucometerb but was below the limit of detection for the instrument. Microscopic evaluation of a Wright's-stained peripheral blood smear (Fig 1) revealed a marked leukocytosis (the estimated nucleated cell count was 50,000 cells/μL). Eighty-one percent of the cells were characterized as poorly differentiated lymphocytes, with 18% nondegenerate neutrophils, and 1% monocytes. There was marked anisocytosis and anisokaryosis within the presumptive lymphoid population. The majority of these cells were large and ranged from 10 to 20 μm in diameter with a high nucleus : cytoplasm ratio and contained a small amount of basophilic, finely granular cytoplasm. The nuclear membrane was ovoid to polygonal and often had a single indention. The chromatin pattern was variably clumped and coarsely granular, and occasionally a single nucleolus was present. Additionally, the erythrocytes appeared mildly decreased in number with unremarkable morphology and no evidence for regeneration (polychromasia and/or basophilic stippling). The platelet concentration and morphology was within normal limits. The microscopic findings were most compatible with lymphoid neoplasia (either stage Vb lymphoma or acute lymphoblastic leukemia) and a mild, nonregenerative anemia. Modified Wright's stain of a blood smear from the cow. Neoplastic lymphoid cells are shown with a high N : C ratio, basophilic cytoplasm, and irregularly shaped nuclei, with variably clumped chromatin. Also present are mature erythrocytes, platelets, and a single segmented neutrophil. The inset shows a neoplastic cell with a deep nuclear cleft. × 1,000 magnification; scale bar = 150 μm. Transthoracic ultrasound revealed no significant abnormalities. Transabdominal ultrasound revealed an enlarged liver extending past the 13th rib. The abomasal wall was disrupted by a cauliflower-shaped mass of mixed echogenicity. No other important abnormalities were noted. Transrectal ultrasound revealed a live fetus of approximately 4 months gestational age with a heart rate of 160 bpm. Although neoplasia was the top differential diagnosis for the cow's problems, and seemed likely given the results of examination of the direct blood smear, treatment was attempted to maintain the cow's life until calving. The cow was treated initially with 500 mL of 50% dextrose IV, flunixin meglumine at 1.1 mg/kg IV, and oxytetracyclinec at 9 mg/kg SC. Polyionic isotonic fluids with added dextrose (Acetated Ringer's solution at a rate of 100 mL/kg/day with 2.5% dextrose) were administered IV for 18 hours. The cow was fed free choice coastal Bermuda grass hay, free choice water, and concentrate (1 pound of 12% sweet feed). The cow remained tachypneic overnight (respiratory rate 44–60 bpm). The following morning, the cow was quiet, alert, and responsive. Rectal temperature was within normal limits (101.5°F), and there was mild tachycardia and tachypnea (heart rate 84 bpm, respiratory rate 36 bpm). Laboratory testing revealed worsening of the anemia and hypoproteinemia (PCV 18%; total protein 5.7 g/dL), resolution of the hyperkalemia and hypochloremia but continued hypoglycemia (glucose, 27 mg/dL). Repeat arterial blood gas analysis revealed mild acidemia (pH 7.34), persistent hyperlactatemia (lactate, 16.4 mmol/L), persistently decreased bicarbonate (bicarbonate, 9.8 mmol/L), persistent hypocapnia (PaCO2, 18.2 mmHg), normal oxygenation (PaO2, 95.7 mmHg), and further decrease in base excess (− 16.4 mmol/L). The lack of improvement in the hyperlactatemia despite volume resuscitation and lack of severe anemia and hypoxemia causing tissue anoxia indicated type B lactic acidosis. The slight improvement in the hypoglycemia despite glucose supplementation indicated impaired gluconeogenesis. The cow became recumbent and lethargic and was euthanized. Gross necropsy revealed enlarged liver, spleen, abomasal wall, and mesenteric lymph nodes were enlarged. The pancreas was normal. There were multiple bleeding ulcers within the abomasal mucosa. Microscopically, there was infiltration of neoplastic lymphoid cells within the liver, spleen, abomasal wall, lymph nodes, and kidneys causing disruption of normal tissue architecture. This was consistent with multicentric lymphoma. Serum AGID was positive for bovine leukosis virus confirming a diagnosis of enzootic bovine lymphosarcoma. Concurrent hypoglycemia and hyperlactatemia secondary to enzootic bovine lymphosarcoma in a cow is unusual. Lactic acidosis is a rare and highly fatal complication of hematopoeitic neoplasms in human patients with a 7% survival rate with chemotherapy.2–7 The precise mechanism is unknown but defective glycolytic processes, liver failure, and renal failure all have been implicated.3 Some neoplastic cells overexpress hexokinase, a rate-limiting glycolytic enzyme with a high affinity for glucose, which may increase uptake and utilization of glucose resulting in overproduction of lactate despite adequate tissue oxygenation.3,7 Upregulation of hexokinase is typically induced by insulin although insulin-like growth factors (IGFs) also induce its expression in neoplastic cells. IGFs have been measured in plasma of humans with lactic acidosis and hypoglycemia secondary to hematopoeitic neoplasms. Total IGF-I, IGF-II, and IGFBP-3 are typically decreased in these patients whereas free forms and IGFBP-1 and IGFBP-2 are typically increased. These findings have led to the hypothesis that glycolytic pathways are altered in tumor cells secondary to the IGF and receptor expression.7 In addition to increased glycolysis in neoplastic cells, hepatic dysfunction has been implicated in the pathogenesis of lactic acidosis. The primary site of lactate metabolism occurs in the liver although other tissues such as skeletal muscle and the kidney are capable of its metabolism.8–10 Lactate is converted either to pyruvate in tissues to enter the Krebs cycle or enters the Cori cycle in the liver to be retransformed to glucose for rapid utilization by peripheral tissues.10 Decreases in liver function occurring in acute hepatic failure can contribute to lactic acidosis although hepatic failure can be present in the absence of lactic acidosis.8 In acute hepatic failure secondary to lymphoma in humans, there is an 83% case fatality rate and 100% of the people had lactic acidosis, 96% had hepatomegaly, and 82, 85, and 97% of cases had increased activity in blood of the liver enzymes alanine aminotransferase, alkaline phosphatase, and aspartate aminotransferase, respectively.5 In these people, the liver was heavily infiltrated with neoplastic cells causing hepatic failure and the syndrome of increased liver enzymes, lactic acidosis, hepatomegaly, and a rapidly fatal course. There are sporadic reports of hypoglycemia and lactic acidosis occurring in people secondary to malignant neoplasms.2–7 Forty-three of 53 patients with lactic acidosis secondary to leukemia and lymphoma had hepatic involvement and 20 of 53 had hypoglycemia.7 Neither the hypoglycemia nor the lactic acidosis responds to glucose, glucagon, or fluid resuscitation therapy in these patients. Many of these patients become tachypneic and have reduced PaCO2 owing to respiratory compensation for metabolic acidosis. Rapid intervention with chemotherapeutic agents is the only effective treatment for the lactic acidosis by causing a reduction in the tumor burden and decreased production of lactate; however, the syndrome is ultimately associated with a poor prognosis. The cow in this report exhibited a syndrome similar to that seen in people with hematopoeitic neoplasms. The hyperlactatemia was not responsive to fluid supplementation suggesting poor tissue perfusion did not play a role in the development of hyperlactatemia and there were no signs of tissue anoxia indicating type B lactic acidosis likely secondary to neoplasia. The minimal improvement in the hypoglycemia with therapy suggested a hypermetabolic process likely secondary to neoplasia. The cow's tachypnea reduced in response to reduction in body temperature but the PaCO2 did not increase concomitantly. Severe concurrent hepatic disease was also present based on laboratory test results, hepatomegaly, and hepatic lymphoma identified on histopathology. It is speculated that decreased hepatic metabolism of lactate into glucose owing to neoplasia-induced hepatic failure and increased rate of glycolysis and lactate production by neoplastic cells were the causes of the hyperlactatemia and hypoglycemia in the cow in the current report. The failure of the cow to respond to treatment is consistent with the syndrome in humans and reflects the poor prognosis associated with this disease. aNuFlor, Schering-Plough Animal Health Corp, Union, NJ bAccu-Check Advantage Meter, Roche Diagnostics, Indianapolis, IN cLiquamycin, Pfizer Animal Health, New York, NY}, number={6}, journal={Journal of Veterinary Internal Medicine}, publisher={Wiley}, author={Elfenbein, J. and Credille, B. and Camus, M. and LeRoy, B. and Blas-Machado, U. and Woolums, A.}, year={2008}, month={Nov}, pages={1441–1443} }