Publications by authors named "Elizabeth W Howerth"

151 Publications

Pathogenesis of Equid Alphaherpesvirus 1 Infection in the Central Nervous System of Mice.

Vet Pathol 2021 Jun 15:3009858211020670. Epub 2021 Jun 15.

28133University of Sao Paulo, Sao Paulo, Brazil.

Equid alphaherpesvirus 1 (EHV-1) causes myeloencephalopathy in horses and occasionally in non-equid species. Although mouse models have been developed to understand EHV-1 pathogenesis, few EHV-1 strains have been identified as highly neurovirulent to mice. The aim of this study was to evaluate the pathogenesis of 2 neurovirulent EHV-1 strains in mice, and to characterize the inflammatory cells and expression of chemokines and the apoptosis marker caspase-3 in the brain of infected mice. C57BL/6J mice were inoculated intranasally with EHV-1 strains A4/72 or A9/92 and evaluated on 1, 2, and 3 days post inoculation (DPI). EHV-1-infected mice showed severe neurological signs at 3 DPI. Ultrastructural analysis revealed numerous viral nucleocapsids and fewer enveloped virions within degenerated and necrotic neurons and in the surrounding neuropil. Histologically, at 3 DPI, there was severe diffuse neuronal degeneration and liquefactive necrosis, prominent microgliosis, and perivascular cuffing composed of CD3 cells (T cells) and Iba-1 cells (macrophages), mainly in the olfactory bulb and ventral portions of the brain. In these areas, moderate numbers of neuroglial cells expressed CCL5 and CCL2 chemokines. Numerous neurons, including those in less affected areas, were immunolabeled for cleaved caspase-3. In conclusion, neurovirulent EHV-1 strains induced a fulminant necrotizing lymphohistiocytic meningoencephalitis in mice, with microgliosis and expression of chemokines and caspase-3. This model will be useful for understanding the mechanisms underlying the extensive neuropathology induced by these viral infections.
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http://dx.doi.org/10.1177/03009858211020670DOI Listing
June 2021

A Retrospective Study of Pathology in Bats Submitted to an Exotic and Zoo Animal Diagnostic Service in Georgia, USA (2008-2019).

J Comp Pathol 2021 May 28;185:96-107. Epub 2021 May 28.

Department of Pathology, Athens, Georgia, USA.

Pathology records of bats submitted to the University of Georgia from managed care settings were reviewed to identify naturally occurring diseases. Fifty-nine cases were evaluated during an 11-year period (2008-2019), including representatives from four families: Pteropodidae (Yinpterochiroptera), Phyllostomidae, Vespertilionidae and Molossidae (Yangochiroptera). Pathology reports were reviewed to determine the primary pathological process resulting in death or the decision to euthanize. Cases were categorized as non-infectious (34/59; 58%), infectious/inflammatory (17/59; 29%) or undetermined due to advanced autolysis (8/59; 14%). Musculoskeletal diseases and reproductive losses were the most frequent pathological processes. Among the infectious processes identified, bacterial infections of the reproductive and haemolymphatic systems were most frequently observed. The first two reports of neoplasia in small flying foxes (Pteropus hypomelanus) are described. Bats under managed care present with a wide range of histopathological lesions. In this cohort, non-infectious disease processes were common.
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http://dx.doi.org/10.1016/j.jcpa.2021.04.010DOI Listing
May 2021

Multinucleate parietal cells and cytoplasmic inclusion bodies in the gastric epithelium of callitrichids.

J Vet Diagn Invest 2021 May 28:10406387211019020. Epub 2021 May 28.

Department of Comparative, Diagnostic, and Population Medicine, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA.

Inclusion bodies (IBs) and multinucleate cells can be associated with viral infections; however, IBs and multinucleate cells have been described in normal tissue and with non-viral disease processes in multiple species. We examined fundic stomach from 50 callitrichids histologically for bi- and multinucleate parietal cells and cytoplasmic IBs in gastric epithelial cells. Callitrichids represented included 6 genera: (4 spp.), (1 sp.), (3 spp.), (1 sp.), (1 sp.), (1 sp.), and 13 unspecified marmosets. Gastric epithelial IBs were present in 46 of 47 (98%) of the callitrichids from which the stomach was sufficiently well preserved to identify IBs. Cytoplasmic IBs were identified in gastric surface pit epithelial cells (43 of 44, 98%), mucous neck cells (43 of 44, 98%), parietal cells (43 of 44, 98%), and chief cells (43 of 44, 98%). The IBs were eosinophilic, ovoid, round, elongate, or variably indented, sometimes slightly refractile, and 1-6 × 1-13 µm. IBs were sometimes perinuclear and molded around the nucleus. Electron microscopy of the gastric epithelium of one marmoset indicated that IBs were composed of intermediate filaments. The IBs did not stain with immunohistochemical markers for cytokeratin AE1/AE3 or vimentin. Binucleate parietal cells were found in 49 of 50 (98%) callitrichids, and multinucleate parietal cells were observed in 40 of 49 (82%) callitrichids. Gastric epithelial cytoplasmic IBs and bi- and multinucleate parietal cells are likely a normal finding in callitrichids, and, to our knowledge, have not been reported previously.
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http://dx.doi.org/10.1177/10406387211019020DOI Listing
May 2021

Clinical tolerance of dexamethasone in New Zealand white rabbits.

Res Vet Sci 2021 May 4;136:259-267. Epub 2021 Mar 4.

Department of Biosciences and Diagnostic Imaging, College of Veterinary Medicine, University of Georgia, Athens, GA, USA. Electronic address:

Rabbits have been a popular pet and research species world-wide. In many clinical and research situations, controlling inflammation is necessary for the health of these animals. One of the first drugs commonly employed in veterinary medicine to suppress inflammatory responses is corticosteroids. Unfortunately, steroid use in rabbits is not universally accepted as they are perceived, based on their potent immunosuppressant activity, to negatively impact quality of life. This is may be due, in part, to the lack of well-developed dosing protocols in these animals. This study evaluated the impact of a 5-day IM dexamethasone (Dex, 0.5 mg/kg) protocol on the immunity and clinical health of the New Zealand rabbit. Through two experiments separated by a 10-day washout period, experiment 1 comprised 5-days of dosing with bleedings on day 0, 3, 5 and 7, where experiment 2 consisted of 5-days of dosing with bleedings on day 0, 3 and 5. Animals were monitored twice daily for changes in clinical health. Hematology, T cell subset phenotype, leukocyte cell cycle, histopathology, phagocytosis and oxidative formation were evaluated. Consistent with other species, 5-day dosing with Dex suppressed leukocytes, in particular the T cells (p ≤ 0.003). Interestingly, rabbits failed to show any adverse clinical signs throughout the entire study. This would imply that a 5-day IM Dex (0.5 mg/kg) dosing protocol is well tolerated by New Zealand white rabbits and could be used in rabbits suffering from inflammatory conditions or disease as long as the animal's immune status is closely monitored.
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http://dx.doi.org/10.1016/j.rvsc.2021.02.015DOI Listing
May 2021

The Effect of Maternal Antibodies on Clinical Response to Infection with Epizootic Hemorrhagic Disease Virus in White-Tailed Deer (Odocoileus virginianus) Fawns.

J Wildl Dis 2021 01;57(1):189-193

Southeastern Cooperative Wildlife Disease Study, Department of Population Health, College of Veterinary Medicine, University of Georgia, 589 D. W. Brooks Drive, Athens, Georgia 30602, USA.

We investigated whether naturally acquired maternal antibodies to epizootic hemorrhagic disease virus serotype 2 (EHDV-2) would protect white-tailed deer (Odocoileus virginianus) fawns against infection and clinical disease following an EHDV-2 challenge. We compared viremia and clinical response in 27-47-d-old, experimentally infected fawns with and without maternally derived antibodies to EHDV-2. Mild to moderate clinical signs were observed in four seronegative (maternal antibody-negative) fawns, which were viremic from 3 to 14 d postinoculation. Individual peak blood virus titers for seronegative fawns ranged from 104.3 to 106.3 median tissue culture infective doses (TCID50)/mL. In contrast, clinical signs were not observed in seropositive (maternal antibody-positive) fawns and a transient low-level viremia (≤102.4 TCID50/mL) occurred in two of six fawns. Our results indicated that the presence of maternally derived EHDV-2 antibodies in fawns prevents or greatly reduces clinical disease and the level and duration of EHDV-2 viremia.
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http://dx.doi.org/10.7589/JWD-D-20-00001DOI Listing
January 2021

Pathology in Practice.

J Am Vet Med Assoc 2021 Mar;258(5):463-465

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http://dx.doi.org/10.2460/javma.258.5.463DOI Listing
March 2021

Pathology in Practice.

J Am Vet Med Assoc 2021 Feb;258(4):383-386

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http://dx.doi.org/10.2460/javma.258.4.383DOI Listing
February 2021

Randomly primed, strand-switching, MinION-based sequencing for the detection and characterization of cultured RNA viruses.

J Vet Diagn Invest 2021 Mar 24;33(2):202-215. Epub 2020 Dec 24.

Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA.

RNA viruses rapidly mutate, which can result in increased virulence, increased escape from vaccine protection, and false-negative detection results. Targeted detection methods have a limited ability to detect unknown viruses and often provide insufficient data to detect coinfections or identify antigenic variants. Random, deep sequencing is a method that can more fully detect and characterize RNA viruses and is often coupled with molecular techniques or culture methods for viral enrichment. We tested viral culture coupled with third-generation sequencing for the ability to detect and characterize RNA viruses. Cultures of bovine viral diarrhea virus, canine distemper virus (CDV), epizootic hemorrhagic disease virus, infectious bronchitis virus, 2 influenza A viruses, and porcine respiratory and reproductive syndrome virus were sequenced on the MinION platform using a random, reverse primer in a strand-switching reaction, coupled with PCR-based barcoding. Reads were taxonomically classified and used for reference-based sequence building using a stock personal computer. This method accurately detected and identified complete coding sequence genomes with a minimum of 20× coverage depth for all 7 viruses, including a sample containing 2 viruses. Each lineage-typing region had at least 26× coverage depth for all viruses. Furthermore, analyzing the CDV sample through a pipeline devoid of CDV reference sequences modeled the ability of this protocol to detect unknown viruses. Our results show the ability of this technique to detect and characterize dsRNA, negative- and positive-sense ssRNA, and nonsegmented and segmented RNA viruses.
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http://dx.doi.org/10.1177/1040638720981019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953086PMC
March 2021

Sparganosis due to sp. (cestoda; Diphyllobothriidae) in captive meerkats ().

Int J Parasitol Parasites Wildl 2020 Dec 18;13:186-190. Epub 2020 Oct 18.

Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia. 501 D.W. Brooks Drive, Athens, GA 30602, USA.

We report three cases of sparganosis due to plerocercoids of the tapeworm sp. in captive meerkats () from a zoo exhibit in the southeastern United States. Two meerkats were euthanized, one due to an uncontrollable seizure and the other due to trauma, and at necropsy cysts containing cestode larvae were observed. A third meerkat had a subcutaneous nodule surgically removed, which contained similar larvae. The third animal died years later, and had numerous cestode larvae in the pleural and peritoneal cavities. The larvae were morphologically identified as plerocercoids of diphyllobothriidean cestodes. On necropsy, multiple nodules, ranging in size from 2.5 to 3.0 cm, were observed in the subcutaneous tissue and muscles. Multifocally, separating skeletal muscle fibers were longitudinal and transversal sections of cestode larva. Histologically, parasitic cysts contained large numbers of neutrophils and macrophages, admixed with proteinaceous material. Molecular and phylogenetic analyses confirmed that specimens from one of the meerkats belonged to the genus and was closely related to plerocercoids isolated from a snake from the United States and wild felids from South America. Meerkats likely became infected by ingesting infected second intermediate hosts, such as amphibians and reptiles that may have entered the exhibit. Management practices that minimize access of meerkats and other susceptible hosts to intermediate hosts should be implemented.
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http://dx.doi.org/10.1016/j.ijppaw.2020.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591330PMC
December 2020

Pathology in Practice.

J Am Vet Med Assoc 2020 Nov;257(9):925-928

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http://dx.doi.org/10.2460/javma.257.9.925DOI Listing
November 2020

A Pilot Study on the Safety of a Novel Antioxidant Nanoparticle Delivery System and Its Indirect Effects on Cytokine Levels in Four Dogs.

Front Vet Sci 2020 30;7:447. Epub 2020 Jul 30.

ProTransit Nanotherapy, LLC, Omaha, NE, United States.

Acute spinal cord injury consists of a primary, traumatic event followed by a cascade of secondary events resulting in ongoing cell damage and death. There is great interest in prevention of these secondary effects to reduce permanent long-term neurologic deficits. One such target includes reactive oxygen species released following injury, which can be enzymatically converted into less harmful molecules by superoxide dismutase and catalase. Canine intervertebral disc herniation has been suggested as a naturally occurring model for acute spinal cord injury and its secondary effects in people. The aims of this study were to test the safety of a novel antioxidant delivery system in four healthy dogs and to indirectly test effect of delivery via cytokine measurement. All dogs experienced adverse events to some degree, with two experiencing adverse events considered to be severe. The clinical signs, including combinations of bradycardia, hypotension, hypersalivation, pale gums, and involuntary urination, were consistent with complement activation-related pseudoallergy (CARPA). CARPA is a well-known phenomenon that has been reported to occur with nanoparticle-based drug delivery, among other documented causes. Two dogs also had mild to moderate changes in their blood cell count and chemistry, including elevated alanine transferase, and thrombocytopenia, which both returned to normal by day 7 post-administration. Cytokine levels trended downwards over the first 3 days, but many were elevated at measurement on day 7. Intradermal testing suggested catalase as a potential cause for reactions. No long-term clinical signs were observed, and necropsy results revealed no concerning pathology. Additional evaluation of this product, including further characterization of reactions to catalase containing components, dose-escalation, and desensitization should be performed before evaluation in clinically affected dogs.
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http://dx.doi.org/10.3389/fvets.2020.00447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406565PMC
July 2020

MYONECROSIS AND DEATH DUE TO PRESUMED MICROCYSTIN TOXICOSIS IN AMERICAN WHITE PELICANS ().

J Zoo Wildl Med 2020 Jun;51(2):407-415

Zoo and Exotic Animal Pathology Service and Infectious Diseases Laboratory, University of Georgia, Athens, GA 30602, USA.

Over a period of 5 mo, seven out of eight American white pelicans () housed on a spring-fed pond at a zoo died or were euthanized. Clinical signs included inability to stand, anorexia, and weight loss. Clinicopathologic findings included heterophilic leukocytosis and elevated creatine kinase and aspartate aminotransferase. Histopathologic findings on all pelicans demonstrated severe, chronic, diffuse rhabdomyofiber degeneration and necrosis, making vitamin E deficiency a differential diagnosis despite routine supplementation. Based on tissue and pond water assays for the cyanobacterial toxin, microcystin, toxicosis is suspected as the inciting cause of death in these cases. We hypothesize that vitamin E exhaustion and resultant rhabdomyodegeneration and cardiomyopathy were sequelae to this toxicosis.
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http://dx.doi.org/10.1638/2019-0117DOI Listing
June 2020

Pathology in Practice.

J Am Vet Med Assoc 2020 Feb;256(3):319-321

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http://dx.doi.org/10.2460/javma.256.3.319DOI Listing
February 2020

Nanoparticles Encapsulating Nitrosylated Maytansine To Enhance Radiation Therapy.

ACS Nano 2020 02 21;14(2):1468-1481. Epub 2020 Jan 21.

Department of Chemistry , University of Georgia , Athens , Georgia 30602 , United States.

Radiotherapy remains a major treatment modality for cancer types such as non-small cell lung carcinoma (or NSCLC). To enhance treatment efficacy at a given radiation dose, radiosensitizers are often used during radiotherapy. Herein, we report a nanoparticle agent that can selectively sensitize cancer cells to radiotherapy. Specifically, we nitrosylated maytansinoid DM1 and then loaded the resulting prodrug, DM1-NO, onto poly(lactide--glycolic)--poly(ethylene glycol) (PLGA--PEG) nanoparticles. The toxicity of DM1 is suppressed by nanoparticle encapsulation and nitrosylation, allowing the drug to be delivered to tumors through the enhanced permeability and retention effect. Under irradiation to tumors, the oxidative stress is elevated, leading to the cleavage of the S-N bond and the release of DM1 and nitric oxide (NO). DM1 inhibits microtubule polymerization and enriches cells at the G2/M phase, which is more radiosensitive. NO under irradiation forms highly toxic radicals such as peroxynitrites, which also contribute to tumor suppression. The two components work synergistically to enhance radiotherapy outcomes, which was confirmed by clonogenic assays and with H1299 tumor-bearing mice. Our studies suggest the great promise of DM1-NO PLGA nanoparticles in enhancing radiotherapy against NSCLC and potentially other tumor types.
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http://dx.doi.org/10.1021/acsnano.9b05976DOI Listing
February 2020

NME5 frameshift variant in Alaskan Malamutes with primary ciliary dyskinesia.

PLoS Genet 2019 09 3;15(9):e1008378. Epub 2019 Sep 3.

Institute of Genetics, Vetsuisse Faculty, University of Bern,Bern, Switzerland.

Primary ciliary dyskinesia (PCD) is a hereditary defect of motile cilia in humans and several domestic animal species. Typical clinical findings are chronic recurrent infections of the respiratory tract and fertility problems. We analyzed an Alaskan Malamute family, in which two out of six puppies were affected by PCD. The parents were unaffected suggesting autosomal recessive inheritance. Linkage and homozygosity mapping defined critical intervals comprising ~118 Mb. Whole genome sequencing of one case and comparison to 601 control genomes identified a disease associated frameshift variant, c.43delA, in the NME5 gene encoding a sparsely characterized protein associated with ciliary function. Nme5-/- knockout mice exhibit doming of the skull, hydrocephalus and sperm flagellar defects. The genotypes at NME5:c.43delA showed the expected co-segregation with the phenotype in the Alaskan Malamute family. An additional unrelated Alaskan Malamute with PCD and hydrocephalus that became available later in the study was also homozygous mutant at the NME5:c.43delA variant. The mutant allele was not present in more than 1000 control dogs from different breeds. Immunohistochemistry demonstrated absence of the NME5 protein from nasal epithelia of an affected dog. We therefore propose NME5:c.43delA as the most likely candidate causative variant for PCD in Alaskan Malamutes. These findings enable genetic testing to avoid the unintentional breeding of affected dogs in the future. Furthermore, the results of this study identify NME5 as a novel candidate gene for unsolved human PCD and/or hydrocephalus cases.
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http://dx.doi.org/10.1371/journal.pgen.1008378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743793PMC
September 2019

INFECTION IN A BLACK-FOOTED FERRET () KIT.

J Zoo Wildl Med 2019 Jun 13;50(2):487-491. Epub 2019 Jun 13.

Louisville Zoological Gardens, Louisville, KY 40213, USA.

A 47-day-old black-footed ferret () kit was found dead in June 2016. Histologic examination revealed pyogranulomatous tubulointerstitial nephritis, pneumonia, and encephalitis, with intralesional microsporidia. Transmission electron microscopic examination showed microsporidia with ultrastructural characteristics consistent with spp. Polymerase chain reaction (PCR) and direct sequencing confirmed the presence of genotype II. This organism has been reported in other Carnivora (i.e., canids, felids, mustelids, procyonids, otariids). In humans, it is generally described as an opportunistic pathogen in immunocompromised individuals. The source of infection in the quarantine facility remains unknown, although two groups of frozen feeder rat kidneys tested positive for genotype II via PCR. Feeding whole prey to various zoo taxa carries some potential disease transmission risk.
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http://dx.doi.org/10.1638/2018-0101DOI Listing
June 2019

Controlled Cortical Impact Leads to Cognitive and Motor Function Deficits that Correspond to Cellular Pathology in a Piglet Traumatic Brain Injury Model.

J Neurotrauma 2019 10 17;36(19):2810-2826. Epub 2019 Jun 17.

Regenerative Bioscience Center, University of Georgia, Athens, Georgia.

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States, with children who sustain a TBI having a greater risk of developing long-lasting cognitive, behavioral, and motor function deficits. This has led to increased interest in utilizing large animal models to study pathophysiologic and functional changes after injury in hopes of identifying novel therapeutic targets. In the present study, a controlled cortical impact (CCI) piglet TBI model was utilized to evaluate cognitive, motor, and histopathologic outcomes. CCI injury (4 m/sec velocity, 9 mm depression, 400 msec dwell time) was induced at the parietal cortex. Compared with normal pigs ( = 5), TBI pigs ( = 5) exhibited appreciable cognitive deficiencies, including significantly impaired spatial memory in spatial T-maze testing and a significant decrease in exploratory behaviors followed by marked hyperactivity in open field testing. Additionally, gait analysis revealed significant increases in cycle time and stance percent, significant decreases in hind reach, and a shift in the total pressure index from the front to the hind limb on the affected side, suggesting TBI impairs gait and balance. Pigs were sacrificed 28 days post-TBI and histological analysis revealed that TBI lead to a significant decrease in neurons and a significant increase in microglia activation and astrogliosis/astrocytosis at the perilesional area, a significant loss in neurons at the dorsal hippocampus, and significantly increased neuroblast proliferation at the subventricular zone. These data demonstrate a strong relationship between TBI-induced cellular changes and functional outcomes in our piglet TBI model that lay the framework for future studies that assess the ability of therapeutic interventions to contribute to functional improvements.
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http://dx.doi.org/10.1089/neu.2019.6405DOI Listing
October 2019

Traumatic Brain Injury Results in Dynamic Brain Structure Changes Leading to Acute and Chronic Motor Function Deficits in a Pediatric Piglet Model.

J Neurotrauma 2019 10 17;36(20):2930-2942. Epub 2019 Jun 17.

Regenerative Bioscience Center, University of Georgia, Athens, Georgia.

Traumatic brain injury (TBI) is a leading cause of death and disability in children. Pediatric TBI patients often suffer from crippling cognitive, emotional, and motor function deficits that have negative lifelong effects. The objective of this study was to longitudinally assess TBI pathophysiology using multi-parametric magnetic resonance imaging (MRI), gait analysis, and histological approaches in a pediatric piglet model. TBI was produced by controlled cortical impact in Landrace piglets. MRI data, including from proton magnetic resonance spectroscopy (MRS), were collected 24 hours and 12 weeks post-TBI, and gait analysis was performed at multiple time-points over 12 weeks post-TBI. A subset of animals was sacrificed 24 hours, 1 week, 4 weeks, and 12 weeks post-TBI for histological analysis. MRI results demonstrated that TBI led to a significant brain lesion and midline shift as well as microscopic tissue damage with altered brain diffusivity, decreased white matter integrity, and reduced cerebral blood flow. MRS showed a range of neurochemical changes after TBI. Histological analysis revealed neuronal loss, astrogliosis/astrocytosis, and microglia activation. Further, gait analysis showed transient impairments in cadence, cycle time, % stance, step length, and stride length, as well as long-term impairments in weight distribution after TBI. Taken together, this study illustrates the distinct time course of TBI pathoanatomic and functional responses up to 12 weeks post-TBI in a piglet TBI model. The study of TBI injury and recovery mechanisms, as well as the testing of therapeutics in this translational model, are likely to be more predictive of human responses and clinical outcomes compared to traditional small animal models.
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http://dx.doi.org/10.1089/neu.2018.6303DOI Listing
October 2019

Alteration of dietary cysteine affects activities of genes of the transsulfuration and glutathione pathways, and development of skin tissues and feather follicles in chickens.

Anim Biotechnol 2020 Jun 5;31(3):203-208. Epub 2019 Apr 5.

NutriGenomics Laboratory, Department of Poultry Science, University of Georgia, Athens, GA, USA.

The dietary requirement for cysteine is not determined in poultry since it is not an essential amino acid. The cysteine need is expected to be met through the transsulfuration pathway where homocysteine, a precursor of methionine, is converted to cysteine. Cysteine is a major component of plumage, and the degree to which cysteine is involved in plumage and other keratized proteins are unknown. We randomly assigned chicks to control and treatment (deficient in cysteine) diets for 49 d. The thickness of the skin layers, feather follicle length, and thickness were measured at days 10, 24, 34, and 49. We also measured the hepatic mRNA expressions of cystathionine beta synthase (), cystathionine γ-lyase (), cysteine dioxygenase (), and glutathione synthetase (. Chickens fed the treatment diet had reduced epidermis thickness and shorter feather follicles compared with the controls. The chicken fed the treatment diet also had increased mRNA expression of and indicating a disruption of the transsulfuration pathway. The treatment chickens also had a decreased hepatic and increased mRNA expressions which are in concordance with the homeostatic regulation of cysteine. Compromised cysteine metabolism could affect thermoregulation and subsequently affect feed efficiency and welfare of the birds.
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http://dx.doi.org/10.1080/10495398.2019.1577253DOI Listing
June 2020

Atypical Chemokine Receptor 1 () in Breast Tumors Is Associated with Survival, Circulating Chemokines, Tumor-Infiltrating Immune Cells, and African Ancestry.

Cancer Epidemiol Biomarkers Prev 2019 04;28(4):690-700

Department of Genetics, Franklin College of Arts and Sciences, University of Georgia, Athens, Georgia.

Background: Tumor-specific immune response is an important aspect of disease prognosis and ultimately impacts treatment decisions for innovative immunotherapies. The atypical chemokine receptor 1 (ACKR1 or DARC) gene plays a pivotal role in immune regulation and harbors several single-nucleotide variants (SNV) that are specific to sub-Saharan African ancestry.

Methods: Using computational The Cancer Genome Atlas (TCGA) analysis, case-control clinical cohort Luminex assays, and CIBERSORT deconvolution, we identified distinct immune cell profile-associated DARC/ACKR1 tumor expression and race with increased macrophage subtypes and regulatory T cells in DARC/ACKR1-high tumors.

Results: In this study, we report the clinical relevance of DARC/ACKR1 tumor expression in breast cancer, in the context of a tumor immune response that may be associated with sub-Saharan African ancestry. Briefly, we found that for infiltrating carcinomas, African Americans have a higher proportion of DARC/ACKR1-negative tumors compared with white Americans, and DARC/ACKR1 tumor expression is correlated with proinflammatory chemokines, CCL2/MCP-1 ( <0.0001) and anticorrelated with CXCL8/IL8 ( <0.0001). Sub-Saharan African-specific DARC/ACKR1 alleles likely drive these correlations. Relapse-free survival (RFS) and overall survival (OS) were significantly longer in individuals with DARC/ACKR1-high tumors ( <1.0 × 10 and <2.2 × 10, respectively) across all molecular tumor subtypes.

Conclusions: regulates immune responses in tumors, and its expression is associated with sub-Saharan African-specific alleles. DARC/ACKR1-positive tumors will have a distinct immune response compared with DARC/AKCR1-negative tumors.

Impact: This study has high relevance in cancer management, as we introduce a functional regulator of inflammatory chemokines that can determine an infiltrating tumor immune cell landscape that is distinct among patients of African ancestry.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450416PMC
April 2019

Chronic granulomatous pneumonia and lung rupture secondary to aspiration of activated charcoal in a French Bulldog.

Vet Clin Pathol 2019 Mar;48(1):67-70

Department of Pathology, University of Georgia, Athens, Georgia.

A 4-year-old, spayed female French Bulldog was presented for respiratory distress and suspected aspiration pneumonia after oral administration of activated charcoal for possible ingestion of a suspected toxic dose of trazodone. The patient had a moderate volume of pleural effusion, which contained free and intracellular black particulate matter consistent with charcoal. Due to presumed charcoal aspiration with subsequent lung rupture, the right middle and right caudal lung lobes were surgically removed. Histology revealed abundant black debris consistent with charcoal and severe granulomatous inflammation. Based on the clinical, gross, and histologic findings, a diagnosis of severe, chronic, locally extensive, aspiration pneumonia and lung rupture with secondary pleuritis and mediastinitis due to charcoal aspiration was made. Aspiration pneumonia is the main complication of activated charcoal administration, which can incite extensive, granulomatous inflammation in the respiratory tract. To the authors' knowledge, this is the first report describing the cytologic and histologic findings associated with inadvertent charcoal aspiration in a veterinary species.
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http://dx.doi.org/10.1111/vcp.12700DOI Listing
March 2019

Effects of an enrofloxacin-silver sulfadiazine emulsion in the ears of rabbits with perforated tympanic membranes.

Am J Vet Res 2019 Apr;80(4):325-334

Objective: To determine whether an enrofloxacin-silver sulfadiazine emulsion (ESS) labeled for treatment of otitis externa in dogs has ototoxic effects in rabbits following myringotomy.

Animals: 6 healthy adult New Zealand White rabbits.

Procedures: Rabbits were anesthetized for brainstem auditory-evoked response (BAER) tests on day 0. Myringotomy was performed, and BAER testing was repeated. Saline (0.9% NaCl) solution and ESS were then instilled in the left and right middle ears, respectively, and BAER testing was repeated prior to recovery of rabbits from anesthesia. Application of assigned treatments was continued every 12 hours for 7 days, and rabbits were anesthetized for BAER testing on day 8. Rabbits were euthanized, and samples were collected for histologic (6 ears/treatment) and scanning electron microscopic (1 ear/treatment) examination.

Results: Most hearing thresholds (11/12 ears) were subjectively increased after myringotomy, with BAER measurements ranging from 30 to 85 dB in both ears. All day 8 hearing thresholds exceeded baseline (premyringotomy) values; results ranged from 30 to 85 dB and 80 to > 95 dB (the upper test limit) in saline solution-treated and ESS-treated ears, respectively. All ESS-treated ears had heterophilic otitis externa, epithelial hyperplasia of the external ear canal, various degrees of mucoperiosteal edema, and periosteal new bone formation on histologic examination. Scanning electron microscopy revealed that most outer hair cells in the ESS-treated ear lacked stereocilia or were absent.

Conclusions And Clinical Relevance: Results supported that ESS has ototoxic effects in the middle ear of rabbits. Further research is needed to confirm these findings. Myringotomized laboratory rabbits may be useful to study ototoxicity of drugs used in human medicine.
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http://dx.doi.org/10.2460/ajvr.80.4.325DOI Listing
April 2019

Evidence of bromethalin toxicosis in feral San Francisco "Telegraph Hill" conures.

PLoS One 2019 18;14(3):e0213248. Epub 2019 Mar 18.

Infectious Diseases Laboratory, University of Georgia, Athens, Georgia, United States of America.

During 2018, four free-ranging conures, from a naturalized flock in San Francisco, presented with a characteristic set of neurologic signs that had been reported in other individuals from this flock. The cause of morbidity or mortality in historic cases has not been identified. From these four subjects, fresh feces were collected during their initial days of hospitalization and submitted to the University of Georgia Infectious Diseases Laboratory and Center for Applied Isotope Studies for bromethalin and desmethyl-bromethalin quantitation. Using High Performance Liquid Chromatography, the laboratory detected bromethalin, a non-anticoagulant, single-dose rodenticide, in fecal samples from three subjects; half of these samples were also positive for desmethyl-bromethalin, bromethalin's active metabolite. In three subjects that died, the UGA laboratory screened brain and liver samples and found bromethalin in all samples; desmethyl-bromethalin was detected in all but one brain sample, which was below the detection limit. Our findings suggest the conures are more resistant to bromethalin than are other species in which bromethalin has been studied, and/or that the conures may be ingesting the toxin at a sublethal dose. More data is needed to better assess the long-term effects of bromethalin on animals exposed at the subacute/chronic levels, and also to better understand the compartmentalization of bromethalin and desmethyl-bromethalin in a wider variety of species.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213248PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422264PMC
December 2019

EXPERIMENTAL INFECTION OF WHITE-TAILED DEER () WITH BLUETONGUE VIRUS SEROTYPE 3.

J Wildl Dis 2019 07 3;55(3):627-636. Epub 2019 Jan 3.

4 Department of Pathology, College of Veterinary Medicine, University of Georgia, 501 D. W. Brooks Dr., Athens, Georgia 30602, USA.

Bluetongue virus serotype 3 (BTV-3) has been found in the US since 1999 and was recently identified in white-tailed deer (WTD; ) found dead in Virginia, US and West Virginia, US in 2016. Bluetongue viruses are known to cause pathologic changes in WTD; however, the relative virulence and pathogenicity of BTV-3 in WTD is unknown. In our study, eight WTD fawns, 6-12 wk old, were needle inoculated subcutaneously with a field isolate of BTV-3, with one fawn shaminoculated as a control during July 2017; all were monitored to determine the pathogenicity of BTV-3 in WTD. All inoculated fawns developed viremias that were first detected on postinoculation day (PID), 3 with peak titers on PID 5 by both quantitative reverse-transcription PCR (qRT-PCR) and virus isolation. The sham-inoculated control fawn also became viremic on PID 12, presumably through contact with infected fawns. Mild clinical signs, including periorbital edema and hyperemia, were first seen on PID 5. None of the fawns developed a significant febrile response, clinical pathology changes, or BTV-3 neutralizing antibodies. The cytokines TNF-α, IL-1β, and IFN-α were not detected by commercial enzyme-linked immunosorbent assays developed for bovids. The absence of severe clinical disease, fibrinogenemia, thrombocytopenia, and leukopenia, along with the lack of seroconversion and a detectable cytokine response during the study period, is atypical when compared to previous experimental BTV serotype infections in WTD but may be related to the young age of these deer, possible attenuation of the BTV-3 strain used, innate resistance or, in some cases to maternally derived antibody to other BTV serotypes.
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http://dx.doi.org/10.7589/2018-06-159DOI Listing
July 2019

Nanoparticle-Laden Macrophages for Tumor-Tropic Drug Delivery.

Adv Mater 2018 Dec 11;30(50):e1805557. Epub 2018 Oct 11.

Department of Chemistry, University of Georgia, Athens, GA, 30602, USA.

Macrophages hold great potential in cancer drug delivery because they can sense chemotactic cues and home to tumors with high efficiency. However, it remains a challenge to load large amounts of therapeutics into macrophages without compromising cell functions. This study reports a silica-based drug nanocapsule approach to solve this issue. The nanocapsule consists of a drug-silica complex filling and a solid silica sheath, and it is designed to minimally release drug molecules in the early hours of cell entry. While taken up by macrophages at high rates, the nanocapsules minimally affect cell migration in the first 6-12 h, buying time for macrophages to home to tumors and release drugs in situ. In particular, it is shown that doxorubicin (Dox) as a representative drug can be loaded into macrophages up to 16.6 pg per cell using this approach. When tested in a U87MG xenograft model, intravenously (i.v.) injected Dox-laden macrophages show comparable tumor accumulation as untreated macrophages. Therapy leads to efficient tumor growth suppression, while causing little systematic toxicity. This study suggests a new cell platform for selective drug delivery, which can be readily extended to the treatment of other types of diseases.
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http://dx.doi.org/10.1002/adma.201805557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506271PMC
December 2018