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Topic:Infectious Disease

Infectious diseases in horses encompass a range of illnesses caused by bacteria, viruses, fungi, or parasites. These diseases can affect various systems within the equine body, leading to symptoms that range from mild discomfort to severe systemic illness. Common infectious diseases in horses include equine influenza, strangles, equine herpesvirus, and West Nile virus. These diseases can be transmitted through direct contact with infected animals, contaminated surfaces, or vectors such as insects. Understanding the mechanisms of transmission, pathogenesis, and immune response is essential for effective prevention and control. This page compiles peer-reviewed research studies and scholarly articles that explore the epidemiology, diagnosis, treatment, and management of infectious diseases in horses.
Clostridium difficile PSI polysaccharide: synthesis of pentasaccharide repeating block, conjugation to exotoxin B subunit, and detection of natural anti-PSI IgG antibodies in horse serum.
Carbohydrate research    March 30, 2013   Volume 378 15-25 doi: 10.1016/j.carres.2013.03.018
Jiao Y, Ma Z, Hodgins D, Pequegnat B, Bertolo L, Arroyo L, Monteiro MA.Clostridium difficile is the most common cause of antimicrobial-associated diarrhea in humans and may cause death. Previously, we discovered that C. difficile expresses three polysaccharides, named PSI, PSII, and PSIII. It has now been established that PSII is a conserved antigen abundantly present on the cell-surface and biofilm of C. difficile. In contrast, the expression of PSI and PSIII appears to be stochastic processes. In this work, the total chemical synthesis of the PSI pentasaccharide repeating unit carrying a linker at the reducing end, α-l-Rhap-(1→3)-β-d-Glcp-(1→4)-[α-l-Rhap...
Prevalence and genetic diversity of piroplasm species in horses and ticks from Tunisia. Ros-García A, M'ghirbi Y, Hurtado A, Bouattour A.The genetic diversity and prevalence of Babesia and Theileria species in the equine population of Tunisia were studied using reverse line blot (RLB) hybridization on blood samples and unfed adult ticks collected from apparently healthy horses from three bioclimatic zones in Tunisia. Piroplasms were identified in 13 of 104 of the horse blood samples analyzed (12.5%) and five genotype groups were identified: Theileria equi group A (nine animals, 8.7%), group C (one animal, 1.0%) and group D (three animals, 2.9%), and Babesia caballi groups A and B (one animal each). All horses from the semi-arid...
A real-time impedance based method to assess Rhodococcus equi virulence.
PloS one    March 28, 2013   Volume 8, Issue 3 e60612 doi: 10.1371/journal.pone.0060612
Miranda-CasoLuengo AA, Miranda-CasoLuengo R, Lieggi NT, Luo H, Simpson JC, Meijer WG.Rhodococcus equi is a facultative intracellular pathogen of macrophages and the causative agent of foal pneumonia. R. equi virulence is usually assessed by analyzing intracellular growth in macrophages by enumeration of bacteria following cell lysis, which is time consuming and does not allow for a high throughput analysis. This paper describes the use of an impedance based real-time method to characterize proliferation of R. equi in macrophages, using virulent and attenuated strains lacking the vapA gene or virulence plasmid. Image analysis suggested that the time-dependent cell response prof...
Molecular determinants of mouse neurovirulence and mosquito infection for Western equine encephalitis virus.
PloS one    March 27, 2013   Volume 8, Issue 3 e60427 doi: 10.1371/journal.pone.0060427
Mossel EC, Ledermann JP, Phillips AT, Borland EM, Powers AM, Olson KE.Western equine encephalitis virus (WEEV) is a naturally occurring recombinant virus derived from ancestral Sindbis and Eastern equine encephalitis viruses. We previously showed that infection by WEEV isolates McMillan (McM) and IMP-181 (IMP) results in high (∼90-100%) and low (0%) mortality, respectively, in outbred CD-1 mice when virus is delivered by either subcutaneous or aerosol routes. However, relatively little is known about specific virulence determinants of WEEV. We previously observed that IMP infected Culex tarsalis mosquitoes at a high rate (app. 80%) following ingestion of an in...
Awareness raised at equine infectious diseases seminar.
The Veterinary record    March 26, 2013   Volume 172, Issue 12 306 doi: 10.1136/vr.f1276
No abstract available
Epidemiological survey of equine influenza in horses in India.
Revue scientifique et technique (International Office of Epizootics)    March 26, 2013   Volume 31, Issue 3 871-875 doi: 10.20506/rst.31.3.2164
Mavadiya SV, Raval SK, Mehta SA, Kanani AN, Vagh AA, Tank PH, Patel PR.A highly contagious virus infection in horses, influenza is the single most important equine respiratory disease in the world. This paper presents details of a one-year study (1 June 2008 to 31 May 2009) to determine the prevalence of equine influenza in the horses of Gujarat State in India. The prevalence of equine influenza A/equi-2 was 12.02%, but none of the samples were positive for equine influenza A/equi-1. The prevalence of equine influenza (A/equi-2) was 15.38%, 11.94%, 10.18%, and 9.09% in horses of the Kathiyawari breed, a non-descript breed, the Marwari breed and the Indian Thoroug...
Repertoire of Theileria equi immunodominant antigens bound by equine antibody.
Molecular and biochemical parasitology    March 26, 2013   Volume 188, Issue 2 109-115 doi: 10.1016/j.molbiopara.2013.03.002
Silva MG, Graça T, Suarez CE, Knowles DP.Theileriosis in horses and cattle is caused by tick-borne Apicomplexa parasites and results in death or life-long infection in their respective hosts. Transmission risk associated with persistent infection severely limits movement of horses and cattle resulting in economic losses. The recent reemergence of Theileria equi infection in U.S. horses demonstrates the continual threat Apicomplexa parasites represent to global animal health. A paucity of data concerning equine immune responses to T. equi, including antigens recognized by antibodies in clinically asymptomatic, persistently infected ho...
Comparison of sampling sites and laboratory diagnostic tests for S. equi subsp. equi in horses from confirmed strangles outbreaks.
Journal of veterinary internal medicine    March 25, 2013   Volume 27, Issue 3 542-547 doi: 10.1111/jvim.12063
Lindahl S, Båverud V, Egenvall A, Aspán A, Pringle J.Strangles is a contagious equine-specific disease caused by Streptococcus equi subsp. equi. Unfortunately, detection of S. equi can fail in up to 40% of horses with strangles. Whereas recent molecular biologic methods and sampling techniques have improved recovery of S. equi optimal sampling methods and laboratory analyses remain ill-defined. Objective: To determine the yield of S. equi from horses with acute strangles in confirmed outbreaks by field-sampling methods subjected to culture and biochemical identification, and real-time PCR directly and after culture. Methods: Fifty-seven horses o...
Babesia equi-induced anemia in a Quarter Horse and subsequent regulatory response.
Journal of the American Veterinary Medical Association    March 23, 2013   Volume 242, Issue 7 992-996 doi: 10.2460/javma.242.7.992
Beard LA, Pelzel AM, Rush BR, Wright AM, Galgut BI, Hennager SG, King AO, Traub-Dargatz JL.A 7-year-old Quarter Horse gelding used for unsanctioned racing was examined because of fever and anorexia. Results: Physical examination revealed fever, tachycardia, and tachypnea. Results of a CBC indicated anemia and mild thrombocytopenia. Results of microscopic examination of a blood smear indicated piroplasms in erythrocytes, consistent with Babesia spp. Regulatory authorities were contacted, and results of serologic testing at the National Veterinary Services Laboratories confirmed acute Babesia equi infection. Results: Equids on the home premises of the index horse were placed under qua...
Mapping the serological prevalence rate of West Nile fever in equids, Tunisia.
Transboundary and emerging diseases    March 21, 2013   Volume 62, Issue 1 55-66 doi: 10.1111/tbed.12077
Bargaoui R, Lecollinet S, Lancelot R.West Nile fever (WNF) is a viral disease of wild birds transmitted by mosquitoes. Humans and equids can also be affected and suffer from meningoencephalitis. In Tunisia, two outbreaks of WNF occurred in humans in 1997 and 2003; sporadic cases were reported on several other years. Small-scale serological surveys revealed the presence of antibodies against WN virus (WNV) in equid sera. However, clinical cases were never reported in equids, although their population is abundant in Tunisia. This study was achieved to characterize the nationwide serological status of WNV in Tunisian equids. In tota...
Glycoprotein H and α4β1 integrins determine the entry pathway of alphaherpesviruses.
Journal of virology    March 20, 2013   Volume 87, Issue 10 5937-5948 doi: 10.1128/JVI.03522-12
Azab W, Lehmann MJ, Osterrieder N.Herpesviruses enter cells either by direct fusion at the plasma membrane or from within endosomes, depending on the cell type and receptor(s). We investigated two closely related herpesviruses of horses, equine herpesvirus type 1 (EHV-1) and EHV-4, for which the cellular and viral determinants routing virus entry are unknown. We show that EHV-1 enters equine epithelial cells via direct fusion at the plasma membrane, while EHV-4 does so via an endocytic pathway, which is dependent on dynamin II, cholesterol, caveolin 1, and tyrosine kinase activity. Exchange of glycoprotein H (gH) between EHV-1...
Indirect fluorescent antibody test and surface antigen ELISAs for antemortem diagnosis of equine protozoal myeloencephalitis.
Journal of veterinary internal medicine    March 20, 2013   Volume 27, Issue 3 596-599 doi: 10.1111/jvim.12061
Johnson AL, Morrow JK, Sweeney RW.Recent research suggests that serum : CSF titer ratios could provide the most accurate antemortem diagnosis of equine protozoal myeloencephalitis (EPM) caused by Sarcocystis neurona. Objective: The purpose of this study was to assess the utility of two commercially available tests, the indirect fluorescent antibody test (IFAT) and the surface antigen 2, 4/3 ELISA (SAG2, 4/3 ELISA), using archived paired serum and CSF samples. Methods: Samples were obtained from 4 types of clinical patients. Confirmed positive cases (n = 9 horses; 11 sample sets) had neurologic deficits and postmortem lesions c...
Concurrent occurrence of human and equine West Nile virus infections in Central Anatolia, Turkey: the first evidence for circulation of lineage 1 viruses.
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases    March 19, 2013   Volume 17, Issue 7 e546-e551 doi: 10.1016/j.ijid.2013.02.005
Ozkul A, Ergunay K, Koysuren A, Alkan F, Arsava EM, Tezcan S, Emekdas G, Hacioglu S, Turan M, Us D.West Nile fever is an important zoonotic infection caused by West Nile virus (WNV), a member of the Flaviviridae. Previous serological data from Turkey suggest widespread WNV circulation. This report includes cases of human and equine WNV infections occurring concurrently, and manifesting as central nervous system infections, in two neighboring provinces of Central Anatolia, Turkey. A partial phylogenetic analysis of the causative virus is given for the first time. Methods: The cases were reported in February (horses) and March (human). Symptoms of the disease were similar in the two species, ...
Diagnosis and isolation of Toxoplasma gondii in horses from Brazilian slaughterhouses. Evers F, Garcia JL, Navarro IT, Zulpo DL, Nino Bde S, Ewald MP, Pagliari S, Almeida JC, Freire RL.This study aimed to investigate anti-Toxoplasma gondii antibodies and to isolate the parasite from the brains of horses processed at slaughterhouses in Brazil. We collected brain and blood samples from 398 horses of various ages, from six Brazilian states. Serum samples were evaluated by indirect fluorescent antibody test (IFAT cut-off titre ≥ 1:64), and brains were submitted to mouse bioassay. Among the 398 horses, positivity for T. gondii was identified in 46 (11.6%) by IFAT and in 14 (3.5%) by mouse bioassay. In 12 of those 14 bioassays, mice were positive only by IFAT (cut-off titre ≥ ...
Monitoring of West Nile virus infections in Germany.
Zoonoses and public health    March 19, 2013   Volume 59 Suppl 2 95-101 doi: 10.1111/zph.12015
Ziegler U, Seidowski D, Angenvoort J, Eiden M, Müller K, Nowotny N, Groschup MH.West Nile virus (WNV) is a flavivirus that is maintained in an enzootic cycle between ornithophilic mosquitoes, mainly of the Culex genus, and certain wild bird species. Other bird species like ravens, jays and raptors are highly susceptible to the infection and may develop deadly encephalitis, while further species of birds are only going through subclinical infection. The objective of this study was to continue in years 2009-2011 the serological and molecular surveillance in wild birds in Germany (see Vector Borne Zoonotic Dis. 10, 639) and to expand these investigations for the first time a...
Identification of a previously undescribed divergent virus from the Flaviviridae family in an outbreak of equine serum hepatitis.
Proceedings of the National Academy of Sciences of the United States of America    March 18, 2013   Volume 110, Issue 15 E1407-E1415 doi: 10.1073/pnas.1219217110
Chandriani S, Skewes-Cox P, Zhong W, Ganem DE, Divers TJ, Van Blaricum AJ, Tennant BC, Kistler AL.Theiler's disease is an acute hepatitis in horses that is associated with the administration of equine blood products; its etiologic agent has remained unknown for nearly a century. Here, we used massively parallel sequencing to explore samples from a recent Theiler's disease outbreak. Metatranscriptomic analysis of the short sequence reads identified a 10.5-kb sequence from a previously undescribed virus of the Flaviviridae family, which we designate "Theiler's disease-associated virus" (TDAV). Phylogenetic analysis clusters TDAV with GB viruses of the recently proposed Pegivirus genus, altho...
Imaging diagnosis-aortic aneurysm and ureteral obstruction secondary to umbilical artery abscessation in a 5-week-old foal. Nogradi N, Magdesian KG, Whitcomb MB, Church M, Spriet M.A 5-week-old foal was evaluated for fever and hematuria of 3 days duration. Cystoscopy localized the blood to be originating from the left ureter. Abdominal ultrasonography revealed left hydronephrosis, hydroureter, and omphaloarteritis of the left umbilical artery with abscess formation that communicated with an arterial structure. Computed tomography (CT) revealed a large aortic aneurysm within the center of the abscess. An exploratory celiotomy was performed and the infection was nonresectable. The prognosis for life was grave; therefore the colt was euthanized. Necropsy findings confirmed ...
Prevalence and risk factors for Equine Infectious Anemia in Poconé municipality, northern Brazilian Pantanal.
Research in veterinary science    March 18, 2013   Volume 95, Issue 1 76-81 doi: 10.1016/j.rvsc.2013.02.011
Borges AM, Silva LG, Nogueira MF, Oliveira AC, Segri NJ, Ferreira F, Witter R, Aguiar DM.Serum samples collected from 547 equids in the Pantanal region of Brazil were evaluated for antibodies to Equine Infectious Anemia Virus (EIAV) by the agar gel immunodiffusion test. Risk factors associated with EIAV seropositivity were evaluated and spatial dependence investigated using a Spatial Lag Model. EIAV prevalence on farms in the Pantanal was 52.0% (13/25) with adjusted prevalence between equids of 31.5% (17.4-48.8% 95% CI). Intra-herd prevalence ranged from 5.0 to 77.0%. Statistical analysis demonstrated that farms and animals in regularly flooded areas had respectively 60 and 146 fo...
Untangling the complex inter-relationships between horse managers’ perceptions of effectiveness of biosecurity practices using Bayesian graphical modelling.
Preventive veterinary medicine    March 13, 2013   Volume 110, Issue 1 37-44 doi: 10.1016/j.prevetmed.2013.02.004
Schemann K, Lewis FI, Firestone SM, Ward MP, Toribio JA, Taylor MR, Dhand NK.On-farm biosecurity practices have been promoted in many animal industries to protect animal populations from infections. Current approaches based on regression modelling techniques for assessing biosecurity perceptions and practices are limited for analysis of the interrelationships between multivariate data. A suitable approach, which does not require background knowledge of relationships, is provided by Bayesian network modelling. Here we apply such an approach to explore the complex interrelationships between the variables representing horse managers' perceptions of effectiveness of on-far...
Knowledge base and effectiveness of online continuing education about foreign animal diseases for equine veterinarians.
Journal of veterinary medical education    March 12, 2013   Volume 40, Issue 1 69-75 doi: 10.3138/jvme.0612-056R
Wiedenheft AM, Traub-Dargatz JL, Gillette SC, O'Keefe GJ, Rao S, Salman MD.The purpose of this study was to assess the effectiveness of two different methods of online education using the knowledge base of African horse sickness (AHS) among US equine veterinarians as a model. An e-mail was sent to US veterinary members of the American Association of Equine Practitioners (AAEP), inviting them to participate in a complementary online educational opportunity. We determined participants' baseline knowledge of AHS by their responses in an AHS case scenario. Participants were then randomly assigned to either a Webinar module or a text-formatted module, followed by an educa...
Equine keratomycosis in Switzerland: a retrospective evaluation of 35 horses (January 2000-August 2011).
Equine veterinary journal    March 12, 2013   Volume 45, Issue 5 608-612 doi: 10.1111/evj.12042
Voelter-Ratson K, Pot SA, Florin M, Spiess BM.Keratomycosis is a severe disease in horses. Geographical differences in fungi causing keratomycosis and susceptibility of the organisms to antifungal drugs exist but few previous publications on this disease originate from Europe. Objective: To retrospectively compare the clinical data of 36 eyes with keratomycosis, diagnosed in 35 horses between January 2000 and August 2011 at the Vetsuisse Faculty of Switzerland. Case history, season, prior treatment, clinical appearance, surgical and medical treatment, treatment duration, and globe survival were evaluated. Methods: Retrospective case serie...
Equine herpesvirus type 1 infection induces procoagulant activity in equine monocytes.
Veterinary research    March 11, 2013   Volume 44, Issue 1 16 doi: 10.1186/1297-9716-44-16
Yeo WM, Osterrieder N, Stokol T.The alphaherpesvirus, equine herpesvirus type 1 (EHV-1), is a highly prevalent cause of equine infectious abortion and encephalomyelopathy. These syndromes have been attributed to ischemic necrosis from thrombosis in placental and neural vessels, although the mechanisms underlying thrombosis are unknown. After inhalation, EHV-1 establishes a peripheral blood mononuclear cell-associated viremia, with monocytes being a target of infection. Monocytes are also the main source of tissue factor (TF) in diseased states. Since TF is the primary activator of coagulation, increased monocyte TF expressio...
Molecular epidemiology of Theileria equi in horses and their association with possible tick vectors in the state of Rio de Janeiro, Brazil.
Parasitology research    March 9, 2013   Volume 112, Issue 5 2017-2025 doi: 10.1007/s00436-013-3360-0
Peckle M, Pires MS, Dos Santos TM, Roier EC, da Silva CB, Vilela JA, Santos HA, Massard CL.The aim of this study was to detect Theileria equi (Laveran 1901) DNA in horses and ticks using real-time PCR and to list the factors associated with infection in animals located in the Seropedica and Petropolis municipalities of the state of Rio de Janeiro. We tested blood samples from 314 horses and samples from 300 ticks, including 191 Amblyomma cajennense, 104 Dermacentor nitens, and 5 Ixodida larvae. Factors inherent to the horse, the ownership, and animal management were obtained from an epidemiological questionnaire and were evaluated in association with the presence of T. equi DNA in t...
The nasal vestibulum is the optimal sampling site for MRSA screening in hospitalised horses.
Veterinary journal (London, England : 1997)    March 7, 2013   Volume 197, Issue 2 415-419 doi: 10.1016/j.tvjl.2013.01.031
Van den Eede A, Hermans K, Van den Abeele A, Floré K, Dewulf J, Vanderhaeghen W, Némeghaire S, Butaye P, Gasthuys F, Haesebrouck F, Martens A.The increased incidence of methicillin-resistant Staphylococcus aureus (MRSA) infection in equine hospitals highlights the need for infection control protocols based on optimal patient screening. In horses, the deep ventral meatus of the nasal cavity is the principal site sampled to detect MRSA. However, in humans, the anterior nares are the preferred sampling site. The objective of this study was to determine the optimal sampling location in the nasal chambers for MRSA in horses by comparing the results obtained from three different locations (the vestibulum, diverticulum and ventral meatus) ...
Understanding the associations between on-farm biosecurity practice and equine influenza infection during the 2007 outbreak in Australia.
Preventive veterinary medicine    March 6, 2013   Volume 110, Issue 1 28-36 doi: 10.1016/j.prevetmed.2013.02.003
Firestone SM, Lewis FI, Schemann K, Ward MP, Toribio JA, Dhand NK.In a previous premises-level case-control study of the 2007 equine influenza outbreak in Australia, the protective effect of several variables representing on-farm biosecurity practices was identified. However, using logistic regression it was not possible to definitively identify individual effects and associations between each of the personal biosecurity measures implemented by horse premises owners and managers in the face of the outbreak. In this study we apply Bayesian network modelling to identify the complex web of associations between these variables, horse premises infection status an...
Venezuelan equine encephalitis replicon particles can induce rapid protection against foot-and-mouth disease virus.
Journal of virology    March 6, 2013   Volume 87, Issue 10 5447-5460 doi: 10.1128/JVI.03462-12
Diaz-San Segundo F, Dias CC, Moraes MP, Weiss M, Perez-Martin E, Owens G, Custer M, Kamrud K, de los Santos T, Grubman MJ.We have previously shown that delivery of the porcine type I interferon gene (poIFN-α/β) with a replication-defective human adenovirus vector (adenovirus 5 [Ad5]) can sterilely protect swine challenged with foot-and-mouth disease virus (FMDV) 1 day later. However, the need of relatively high doses of Ad5 limits the applicability of such a control strategy in the livestock industry. Venezuelan equine encephalitis virus (VEE) empty replicon particles (VRPs) can induce rapid protection of mice against either homologous or, in some cases, heterologous virus challenge. As an alternative approach ...
Detection of Theileria equi and Babesia caballi infections in Venezuelan horses using Competitive-Inhibition ELISA and PCR.
Veterinary parasitology    March 5, 2013   Volume 196, Issue 1-2 37-43 doi: 10.1016/j.vetpar.2013.02.004
Rosales R, Rangel-Rivas A, Escalona A, Jordan LS, Gonzatti MI, Aso PM, Perrone T, Silva-Iturriza A, Mijares A.The focus of this study was the detection of equine piroplasmosis in Distrito Capital, Miranda, Aragua, Guárico and Apure States from Venezuela, using two methods: Competitive-Inhibition ELISA and multiplex PCR and the analysis of the possible differences in occurrence in relation to the primary purpose of the horses, which is related to varied degrees of exposure to tick. Antibody levels to Babesia caballi and Theileria equi were assessed in 694 equine serum samples using Competitive-Inhibition ELISA, while PCR assays were performed in 136 horses, using two sets of oligonucleotides to establ...
Clinical observations and management of a severe equine herpesvirus type 1 outbreak with abortion and encephalomyelitis.
Acta veterinaria Scandinavica    March 5, 2013   Volume 55, Issue 1 19 doi: 10.1186/1751-0147-55-19
Walter J, Seeh C, Fey K, Bleul U, Osterrieder N.Latent equine herpesvirus type 1 (EHV-1) infection is common in horse populations worldwide and estimated to reach a prevalence nearing 90% in some areas. The virus causes acute outbreaks of disease that are characterized by abortion and sporadic cases of myeloencephalopathy (EHM), both severe threats to equine facilities. Different strains vary in their abortigenic and neuropathogenic potential and the simultaneous occurrence of EHM and abortion is rare. In this report, we present clinical observations collected during an EHV-1 outbreak caused by a so-called "neuropathogenic" EHV-1 G(2254)/D(...
Eliminating infectious diseases of livestock: a metapopulation model of infection control.
Theoretical population biology    March 4, 2013   Volume 85 63-72 doi: 10.1016/j.tpb.2013.02.002
Glass K, Barnes B.When novel disease outbreaks occur in livestock, policy makers must respond promptly to eliminate disease, and are typically called on to make control decisions before detailed analysis of disease parameters can be undertaken. We present a flexible metapopulation model of disease spread that incorporates variation in livestock density and includes occasional high-mixing locations or events, such as markets or race meetings. Using probability generating functions derived from this branching process model, we compare the likely success of reactive control strategies in eliminating disease spread...
Retrospective study on equine uterine fungal isolates and antifungal susceptibility patterns (1999-2011).
Equine veterinary journal. Supplement    March 2, 2013   Issue 43 84-87 doi: 10.1111/j.2042-3306.2012.00608.x
Beltaire KA, Cheong SH, Coutinho da Silva MA.Knowledge of commonly encountered fungi infecting the mare's reproductive tract and their respective drug susceptibilities should improve treatment efficacy in mares with fungal endometritis. This is particularly important when practitioners need to start empiric treatment before culture results are complete. Objective: To report the spectrum of fungal isolates from uterine samples from mares with reproductive problems and their respective antifungal susceptibilities. Methods: Equine uterine samples submitted to the Cornell University Animal Health Diagnostic Centre for fungal culture between ...