Life, Death, and Humanity in Veterinary Medicine: Is it Time to Embrace the Humanities in Veterinary Education?

Medical humanities is a multidisciplinary, interdisciplinary field of study that has experienced explosive growth in the United States since the 1960s. Two key components of medical humanities include first, the use of literature, poetry, and visual arts in the education of medical students, and second, the representation or examination of medical culture by scholars in the humanities, arts, and social sciences such as literary and film creators, sociologists, and anthropologists. The American Association of Medical Colleges recently reported that as of 2018, approximately 94% of medical schools had core or elective humanities offerings in their curricula. The examination of the medical milieu by scholars across the humanities has resulted in the emergence of important specialty fields such as end-of-life care, disability studies, and health disparities research. Veterinary medicine has been slow to embrace the humanities as relevant to our profession and to the education of our students. Only sporadic, isolated attempts to document the value of the arts and humanities can be found in the veterinary literature, and valuable observations on our profession made by scholars in diverse disciplines of the humanities are largely buried in publications not often accessed by veterinarians. Here a case is made that the time is right for the emergence of a more cohesive field of veterinary humanities. Embracing the observations of humanities scholars who engage with our profession, and appreciating the ways in which the humanities themselves are effective tools in the education of veterinary professionals, will bring many benefits to our evolving profession.

Genetics, Evolution, and Physiology of Donkeys and Mules.

The genus Equus is made up of donkeys, horses, and zebras. Despite significant variation in chromosome number across these species, interspecies breeding results in healthy, although infertile, hybrid offspring. Most notable among these are the horse-donkey hybrids, the mule and hinny. Donkeys presently are used for everything from companion animals to beasts of burden. Although closely related from an evolutionary standpoint, differences in anatomy and physiology preclude the assumption that they can be treated identically to the domestic horse. Veterinarians should be aware of these differences and adjust their practice accordingly.

Ectopic Trophoblast Allografts in the Horse Resist Destruction by Secondary Immune Responses.

Invasive trophoblast from Day 34 horse conceptuses survives in extrauterine sites in allogeneic recipients that are immunologically naive to donor major histocompatibility complex class I antigens. The ectopic trophoblast retains its in utero characteristics, including similar lifespan, physiologic effect of its secreted product (equine chorionic gonadotropin) upon the recipient's ovaries, and induction of host immune responses. Immunologic memory has not been considered previously in this experimental system. We hypothesized that primary exposure to ectopic trophoblast would affect the recipient's immune status such that the survival time of subsequent transplants would be altered. Secondary transplant lifespans could be shortened by destructive memory responses, as has been observed in ectopic trophoblast studies in rodents, or lengthened, as occurs when male skin grafts follow multiple syngeneic pregnancies in mice. Eight mares received two closely spaced trophoblast transplants. Both grafts for each recipient were obtained from conceptuses sired by the same stallion to provide consistency in histocompatibility antigen exposure. Donor stallions were major histocompatibility complex class I homozygotes. Cytotoxic antibody production was tracked to monitor recipients' immune responses to the transplants. Detection of serum equine chorionic gonadotropin was used as a proxy for transplant lifespan. There was no significant difference between the distributions of primary and secondary transplant lifespans, despite evidence of immunologic memory. These data demonstrate that secondary ectopic trophoblast transplants in horses do not experience earlier destruction or prolonged survival following immune priming of recipients. Mechanisms responsible for the eventual demise of the transplants remain unperturbed by secondary immune responses or chronic antigenic exposure.

Equine allogeneic bone marrow-derived mesenchymal stromal cells elicit antibody responses in vivo.

INTRODUCTION: This study tested the hypothesis that Major Histocompatibility Complex (MHC) incompatible equine mesenchymal stromal cells (MSCs) would induce cytotoxic antibodies to donor MHC antigens in recipient horses after intradermal injection. No studies to date have explored recipient antibody responses to allogeneic donor MSC transplantation in the horse. This information is critical because the horse is a valuable species for assessing the safety and efficacy of MSC treatment prior to human clinical application. METHODS: Six MHC heterozygote horses were identified as non-ELA-A2 haplotype by microsatellite typing and used as allogeneic MHC-mismatched MSC recipients. MHC homozygote horses of known ELA-A2 haplotype were used as MSC and peripheral blood leukocyte (PBL) donors. One MHC homozygote horse of the ELA-A2 haplotype was the recipient of ELA-A2 donor MSCs as an MHC-matched control. Donor MSCs, which were previously isolated and immunophenotyped, were thawed and culture expanded to achieve between 30x10(6) and 50x10(6) cells for intradermal injection into the recipient's neck. Recipient serum was collected and tested for the presence of anti-donor antibodies prior to MSC injection and every 7 days after MSC injection for the duration of the 8-week study using the standard two-stage lymphocyte microcytotoxicity dye-exclusion test. In addition to anti-ELA-A2 antibodies, recipient serum was examined for the presence of cross-reactive antibodies including anti-ELA-A3 and anti-RBC antibodies. RESULTS: All MHC-mismatched recipient horses produced anti-ELA-A2 antibodies following injection of ELA-A2 MSCs and developed a wheal at the injection site that persisted for the duration of the experiment. Anti-ELA-A2 antibody responses were varied both in terms of strength and timing. Four recipient horses had high-titered anti-ELA-A2 antibody responses resulting in greater than 80% donor PBL death in the microcytotoxicity assays and one of these horses also developed antibodies that cross-reacted when tested on lymphocyte targets from a horse with an unrelated MHC type. CONCLUSIONS: Allogeneic MSCs are capable of eliciting antibody responses in vivo that can be strong and also cross-reactive with MHC types other than that of the donor. Such responses could limit the effectiveness of repeated allogeneic MSC use in a single horse, and could also result in untoward inflammatory responses in recipients.

Patterning and post-patterning modes of evolutionary digit loss in mammals.

A reduction in the number of digits has evolved many times in tetrapods, particularly in cursorial mammals that travel over deserts and plains, yet the underlying developmental mechanisms have remained elusive. Here we show that digit loss can occur both during early limb patterning and at later post-patterning stages of chondrogenesis. In the 'odd-toed' jerboa (Dipus sagitta) and horse and the 'even-toed' camel, extensive cell death sculpts the tissue around the remaining toes. In contrast, digit loss in the pig is orchestrated by earlier limb patterning mechanisms including downregulation of Ptch1 expression but no increase in cell death. Together these data demonstrate remarkable plasticity in the mechanisms of vertebrate limb evolution and shed light on the complexity of morphological convergence, particularly within the artiodactyl lineage.

IL-22 is expressed by the invasive trophoblast of the equine (Equus caballus) chorionic girdle.

The invasive trophoblast cells of the equine placenta migrate into the endometrium to form endometrial cups, dense accumulations of trophoblast cells that produce equine chorionic gonadotropin between days 40 and 120 of normal pregnancy. The mechanisms by which the trophoblast cells invade the endometrium while evading maternal immune destruction are poorly defined. A gene expression microarray analysis performed on placental tissues obtained at day 34 of gestation revealed a >900-fold upregulation of mRNA encoding the cytokine IL-22 in chorionic girdle relative to noninvasive chorion. Quantitative RT-PCR assays were used to verify high expression of IL-22 in chorionic girdle. Additional quantitative RT-PCR analysis showed a striking increase in IL-22 mRNA expression in chorionic girdle from days 32 to 35 and an absence of IL-22 expression in other conceptus tissues. Bioinformatic analysis and cDNA sequencing confirmed the predicted length of horse IL-22, which carries a 3' extension absent in IL-22 genes of humans and mice, but present in the cow and pig. Our discovery of IL-22 in the chorionic girdle is a novel finding, as this cytokine has been previously reported in immune cells only. IL-22 has immunoregulatory functions, with primary action on epithelial cells. mRNA of IL-22R1 was detected in pregnant endometrium at levels similar to other equine epithelia. Based upon these findings, we hypothesize that IL-22 cytokine produced by the chorionic girdle binds IL-22R1 on endometrium, serving as a mechanism of fetal-maternal communication by modulating endometrial responses to trophoblast invasion.

Gastric and enteric phytobezoars caused by ingestion of persimmon in equids.

CASE DESCRIPTION-13 equids (10 horses, 2 donkeys, and 1 pony) were examined for signs of colic (n = 7), weight loss (6), anorexia (3), and diarrhea (2). Ten equids were evaluated in the fall (September to November). Seven equids had a history of persimmon ingestion. CLINICAL FINDINGS-A diagnosis of phytobezoar caused by persimmon ingestion was made for all equids. Eight equids had gastric persimmon phytobezoars; 5 had enteric persimmon phytobezoars. Gastroscopy or gastroduodenoscopy revealed evidence of persimmon ingestion in 8 of 10 equids in which these procedures were performed. TREATMENT AND OUTCOME-2 of 13 equids were euthanatized prior to treatment. Supportive care was instituted in 11 of 13 equids, including IV administration of fluids (n = 8) and treatment with antimicrobials (5), NSAIDs (5), and gastric acid suppressants (4). Persimmon phytobezoar-specific treatments included dietary modification to a pelleted feed (n = 8); oral or nasogastric administration of cola or diet cola (4), cellulase (2), or mineral oil (2); surgery (4); and intrapersimmon phytobezoar injections with acetylcysteine (1). Medical treatment in 5 of 7 equids resulted in resolution of gastric persimmon phytobezoars. Seven of 8 equids with gastric persimmon phytobezoars and 1 of 5 equids with enteric persimmon phytobezoars survived > 1 year after hospital discharge. CLINICAL RELEVANCE-Historical knowledge of persimmon ingestion in equids with gastrointestinal disease warrants gastroduodenoscopy for evaluation of the presence of persimmon phytobezoars. In equids with gastric persimmon phytobezoars, medical management (including administration of cola or diet cola and dietary modification to a pelleted feed) may allow for persimmon phytobezoar dissolution.

The effect of siRNA treatment on experimental equine herpesvirus type 1 (EHV-1) infection in horses.

Available vaccines fail to induce lasting and protective immunity to equine herpesvirus 1 (EHV-1) associated diseases. RNA interference is a novel approach showing promise for therapeutic use in outbreak situations. This study examined the effect of small interfering RNA (siRNA) on clinical signs as well as the presence of live virus and viral DNA in nasal secretions and peripheral blood mononuclear cells (PBMCs) in horses experimentally infected with EHV-1. siRNA targeting two EHV-1 genes (glycoprotein B and the origin binding protein) was administered 12h before and 12h after intranasal infection with EHV-1. Control horses received siRNA targeting firefly luciferase. A significantly smaller proportion (0/10) of horses receiving siRNA targeting viral genes required euthanasia due to intractable neurologic disease as compared to horses in the control group (3/4; p=0.01). There was no significant difference in the presence of live virus or viral DNA in the nasal secretions or PBMCs between the two groups. Future studies are necessary to define the relative contributions of host and virus factors in the development of the neurological form of the infection and to determine an optimal dosing regimen for metaphylactic or therapeutic use of siRNA for treating EHV-1 infection.

Intra-abdominal hypertension in two adult horses.

OBJECTIVE: To describe the clinical and pathological findings in 2 adult horses with documented increases in intra-abdominal pressure (IAP), and to describe the direct puncture technique used to measure this pressure. SERIES SUMMARY: Two adult horses developed increases in IAP secondary to large-volume abdominal effusion. A 9-year-old Quarter Horse cross gelding was presented for evaluation of urinary and neurologic signs. Abdominal ultrasonographic examination showed a hepatic abscess along with abdominal effusion. A 4-year-old Quarter Horse gelding was presented for evaluation of castration complications. A castration site infection extended into surrounding tissues, resulting in peritonitis, abdominal effusion, and severe cellulitis of the limbs. IAP measured in both horses was increased relative to reported equine reference values. Changes in hemodynamic parameters in both horses, notably increased central venous pressure, were consistent with those seen in other species in which intra-abdominal hypertension (IAH) and its sequellae have been documented. NEW OR UNIQUE INFORMATION PROVIDED: Extensive research and clinical literature guides management of humans with IAH and abdominal compartment syndrome. Knowledge of these conditions in companion animal and large domestic species is less well developed. Recent research has established reference values for standing, sedated and recumbent, anesthetized horses. Detailed reports of equine clinical cases of IAH have not been reported in the literature. This report provides information on the clinical, hemodynamic, and pathologic characteristics of 2 horses with measured increases in IAP, and describes the direct puncture technique used to perform these measurements.

Effective treatment of respiratory alphaherpesvirus infection using RNA interference.

BACKGROUND: Equine herpesvirus type 1 (EHV-1), a member of the Alphaherpesvirinae, is spread via nasal secretions and causes respiratory disease, neurological disorders and abortions. The virus is a significant equine pathogen, but current EHV-1 vaccines are only partially protective and effective metaphylactic and therapeutic agents are not available. Small interfering RNAs (siRNA's), delivered intranasally, could prove a valuable alternative for infection control. siRNA's against two essential EHV-1 genes, encoding the viral helicase (Ori) and glycoprotein B, were evaluated for their potential to decrease EHV-1 infection in a mouse model. METHODOLOGY/PRINCIPAL FNDINGS: siRNA therapy in vitro significantly reduced virus production and plaque size. Viral titers were reduced 80-fold with 37.5 pmol of a single siRNA or with as little as 6.25 pmol of each siRNA when used in combination. siRNA therapy in vivo significantly reduced viral replication and clinical signs. Intranasal treatment did not require a transport vehicle and proved effective when given up to 12 h before or after infection. CONCLUSIONS/SIGNIFICANCE: siRNA treatment has potential for both prevention and early treatment of EHV-1 infections.

Bone marrow necrosis and myelophthisis: manifestations of T-cell lymphoma in a horse.

A 14-year-old spayed American Paint mare was evaluated for mild colic, anorexia, pyrexia, and pancytopenia. Physical examination revealed mild tachycardia, tachypnea, and pale mucous membranes. Serial laboratory analyses revealed progressive pancytopenia, hyperfibrinogenemia, and hyperglobulinemia. A few large atypical cells were observed in peripheral blood smears. Results of tests for equine infectious anemia and antipenicillin antibody were negative. Serum protein electrophoresis indicated a polyclonal gammopathy. Smears of bone marrow aspirates contained hypercellular particles, but cell lines could not be identified because the cells were karyolytic, with pale basophilic smudged nuclei and lack of cellular detail. A diagnosis of bone marrow necrosis was made. Treatment consisted of antimicrobials, nonsteroidal anti-inflammatory drugs, and corticosteroids. The pyrexia resolved; however, the pancytopenia progressively worsened and petechiation and epistaxis developed. The horse was humanely euthanized. Postmortem examination revealed a diffuse round cell neoplasm infiltrating the kidneys, spleen, lymph nodes, lungs, and bone marrow. Immunophenotyping results (CD3+, CD79alpha-) indicated the neoplastic cells were of T-cell lineage. Infiltration of lymphoma cells into the bone marrow appeared to have resulted in severe myelophthisis and bone marrow necrosis. Bone marrow necrosis has been associated previously with lymphoma in humans and dogs. To our knowledge, this is the first reported case of lymphoma resulting in bone marrow necrosis in a horse.

A model euthanasia workshop: one class's experience at Tufts University.

Performing euthanasia is likely one of the most challenging tasks a veterinarian faces. Four students at Tufts University School of Veterinary Medicine felt that they and their classmates needed additional training on this subject. They informally surveyed their classmates to determine what topics and formats the students desired. The findings were used to develop the Euthanasia Workshop at the university, a voluntary series of lectures and discussions on technical and emotional issues relating to euthanasia. The four students then informally surveyed 30 North American veterinary colleges to determine the scope of euthanasia training in other veterinary programs. They found that euthanasia, while often covered within other courses, is rarely taught as a stand-alone course.

Demographic and clinical characteristics of geriatric horses: 467 cases (1989-1999).

OBJECTIVE: To describe the demographic and clinical characteristics of a population of geriatric horses. DESIGN: Retrospective study. ANIMALS: 467 horses that were > or = 20 years of age. PROCEDURE: Medical records of 539 geriatric horses that were evaluated at a university large animal hospital between 1989 and 1999 were reviewed. Data collected included signalment, reason for evaluation, specific diagnoses, surgical procedures, inpatient or outpatient care, duration of hospitalization, and outcome. RESULTS: 467 horses met the criteria for inclusion in the study. Horses that were > or = 20 years of age comprised 2.2 and 12.5% of horses evaluated during 1989 and 1999, respectively. Pony breeds were significantly overrepresented in the > or = 30-years-of-age group. Gastrointestinal tract, musculoskeletal, and respiratory tract problems were most frequently reported. Colic was the most common clinical sign, followed by lameness. Diagnoses made most frequently included pituitary dysfunction, strangulating lipoma of the small intestine, laminitis, heaves, large colon impaction, and gastric ulcers. Pituitary dysfunction was significantly more prevalent in horses that were > 30 years of age. Laminitis was significantly associated with the presence of pituitary dysfunction. CONCLUSIONS AND CLINICAL RELEVANCE: It was difficult to assess association of age with illnesses identified in these horses. Demographic data and information regarding common diseases of horses that are > or = 20 years of age are limited but will become increasingly important as this geriatric population increases.

Assessment of clinical characteristics, management practices, and activities of geriatric horses.

OBJECTIVE: To describe the demographic and clinical characteristics, management practices, and owner perception of a population of geriatric horses, and to compare these data with findings in a group of younger horses. DESIGN: Original study. ANIMALS: 218 horses. PROCEDURE: Data were collected via a survey tool from owners of 165 horses that were > or = 20 years of age and 53 horses that were < 20 years of age. RESULTS: Compared with young horses, the geriatric group included a significantly greater number of ponies; geriatric horses were also more likely to have a history of colic, dental disease, tumors, lameness, and pituitary disease, but not laminitis, diarrhea, allergies, respiratory tract disease, thyroid disease, or fractures. Horses that had participated in Western equestrian disciplines were more likely to have a history of lameness. Among old horses, those with pituitary dysfunction were more likely to have a history of laminitis than those without pituitary dysfunction. Geriatric horses were more likely to have long hair and shedding abnormalities than were younger horses. Owners perceived their horses as old at approximately 22 years of age. In horses older than 16.5 years of age, age was a negative factor in the purchase of horses. CONCLUSIONS AND CLINICAL RELEVANCE: Geriatric and young horses share some similar health problems, but old horses have distinct health problems and veterinary medical requirements. The management and athletic history of horses may influence health as they age.