Here we characterized the murine dextran sulfate sodium (DSS) model of acute colitis. Specifically, we evaluated azithromycin and metronidazole treatment regimens to assess their effects on animal wellbeing, pathologic changes, barrier function, cytokine and chemokine profiles, and neutrophil migration in colon tissue. Azithromycin treatment significantly reduced the severity of colitis, as assessed through body weight change, water consumption, macroscopic lesions, and animal behaviors (activity level, climbing, and grooming), but did not alter food consumption or feeding behavior. Mucosal barrier function (evaluated by using FITC-labeled dextran) was decreased after DSS exposure; azithromycin did not significantly alter barrier function in mice with colitis, whereas metronidazole exacerbated the colitis-related deficit in barrier function. In addition, metronidazole appeared to exacerbate disease as assessed through water consumption and animal behaviors (overall activity, climbing, grooming, and drinking) but had no effect on weight loss, macroscopic lesions, or eating behavior. Pathologic changes were typical for DSS treatment. Antibiotic treatment resulted in reduced levels of proinflammatory cytokines and chemokines and decreased neutrophil adhesion and emigration in DSS-exposed mice. The results highlight the importance of clinical and behavioral assessments in addition to laboratory evaluation as tools to evaluate animal welfare and therapeutic efficacy in disease models. Data from this study suggest that azithromycin may convey some benefits in the mouse DSS colitis model through modulation of the immune response, including neutrophil migration into tissues, whereas metronidazole may exacerbate colitis.

Transgenic TgMISIIR-TAg (TAg) mice express the oncogenic virus SV40 in Mullerian epithelial cells. Female TAg mice spontaneously develop epithelial ovarian carcinoma, the most common type of ovarian cancer in women. Female TAg mice are infertile, but the reason has not been determined. We therefore investigated whether female TAg mice undergo puberty, demonstrate follicular development, maintain regular cycles, and ovulate. Ovarian cancers in women commonly develop after menopause. The occupational chemical 4-vinylcyclohexene diepoxide (VCD) accelerates follicle degeneration in the ovaries of rats and mice, causing early ovarian failure. We therefore used VCD dosing of mice to develop an animal model for menopause. The purpose of this study was to characterize reproductive parameters in female TAg mice and to investigate whether the onset of ovarian failure due VCD dosing differed between female TAg and WT C57BL/6 mice. As in WT female mice, TAg female mice underwent puberty (vaginal opening) and developed cyclicity in patterns that were similar between the groups. Vehicle-only TAg mice had fewer ovulations (numbers of corpora lutea) than WT animals. VCD exposure delayed the onset of puberty (day of first estrus) in TAg as compared with WT mice. Morphologic evaluation of ovaries revealed many more degenerating follicles in TAg mice than WT mice, and more VCD-dosed TAg mice were in ovarian failure than VCD-dosed WT mice. These results suggest that despite showing similar onset of sexual maturation, TAg mice have increased follicular degeneration and fewer ovulations than WT. These features may contribute to the inability of female TAg mice to reproduce.

Canine histiocytic sarcoma is a highly aggressive and metastatic hematopoietic neoplasm that responds poorly to currently available treatment regimens. Our goal was to establish a clinically relevant xenograft mouse model to assess the preclinical efficacy of novel cancer treatment protocols for histiocytic sarcoma. We developed an intrasplenic xenograft mouse model characterized by consistent tumor growth and development of metastasis to the liver and other abdominal organs. This model represents the metastatic or disseminated form of canine histiocytic sarcoma, which is considered the most clinically challenging form of the disease. Transfection of tumor cells with a luciferase vector supported the use of in vivo bioluminescence imaging to track tumor progression over time and to assess the response of this murine model to novel chemotherapeutic agents. Dasatinib treatment of the mice with intrasplenic xenografts decreased tumor growth and increased survival times, compared with mice treated with vehicle only. Our findings indicate the potential of dasatinib for the treatment of histiocytic sarcoma in dogs and for similar diseases in humans. These results warrant additional studies to clinically test the efficacy of dasatinib in dogs with histiocytic sarcoma.

Ketamine is one of the most commonly used anesthetics in human and veterinary medicine, but its clinical effectiveness is often compromised due to tolerance to its anesthetic effects. Although ketamine tolerance has been demonstrated in a number of behavioral measures, no published work has investigated tolerance to ketamine's anesthetic effects other than duration of anesthesia. In addition, a reported practice in anesthesiology is to alter anesthetic doses for procedures when the patient has a history of drug abuse. Empirically investigating the effects of administration of a drug of abuse on ketamine's potency and efficacy to produce anesthesia could help in the creation of anesthetic plans that maximize safety for both clinicians and patients. The goal of the current study was to test the effects of repeated administration of ketamine, morphine, or cocaine on ketamine's ability to produce anesthesia. In 2 studies, male Sprague–Dawley rats received daily injections of ketamine (32 or 100 mg/kg IP), morphine (3.2 or 5.6 mg/kg IP), or cocaine (3.2 or 10 mg/kg IP) for 14 consecutive days and then were tested on day 15 for ketamine-induced anesthesia by using a cumulative-dosing procedure (32 to 320 mg/kg IP). Chronic treatment with either ketamine or morphine—but not cocaine—produced tolerance to ketamine's anesthetic effects in a dose-dependent manner. These results suggest that ketamine's clinical effectiveness as an anesthetic will vary as a function of its history of use. Furthermore, given that chronic morphine administration produced tolerance to ketamine's anesthetic effects, various pain medications may reduce ketamine's effectiveness for anesthesia.

Stress can influence the secretion of neuroendocrine mediators, thereby exposing immune cells to altered signaling and interactions. Here we investigated the synergetic effect of stress and environmental enrichment on the immune response of Long–Evans rats. Subjects (n = 46) were assigned to 5 treatment groups: acute compared with chronic stress with or without environmental enrichment, plus an unmanipulated control group. Animals also were classified as active, passive, and flexible copers according to back-test assessment. Rats were exposed to enrichment in an open-field containing objects in different areas for 30 min 3 times each week, thus modeling the effects of a temporary increase in environmental stimuli. Animals assigned to chronic stress groups were exposed to predator sound stressors for 30 min daily, whereas animals assigned to acute stress groups were exposed once each week. After 7 wk, a dermal punch biopsy was administered to activate the immune response, after which rats were challenged through a forced swim test. Biologic samples were collected to measure corticosterone, dehydroepiandrosterone (DHEA), oxytocin, testosterone, and the cytokines IL6 and IL10. Rats exposed to chronic stress had lower DHEA:corticosterone ratios, suggesting increased allostatic load. Enrichment exposure modulated these effects, lowering overall corticosterone and testosterone levels and increasing DHEA and oxytocin levels in animals exposed to the predator sound. The immune response was decreased in rats exposed to chronic stress, but the effect of environmental enrichment helped to mitigate the negative influence on cells producing IL6. Combining acute stress and exposure to an enriched environment returned a healthier profile in terms of both immune activation and stress regulation. By using a multidimensional scaling model, we found that a combination of 'good' stress and exposure to brief sessions of enriching stimuli can reliably predict health in Long–Evans rats.

Melanoma is an immunogenic tumor that can metastasize quickly to proximal and distal sites, thus complicating the application of therapeutic modalities. Numerous mouse model systems have been used to gain understanding of the immunobiology and metastatic potential of melanoma. Here, we report the optimization of a syngeneic mouse melanoma model protocol using the mouse B16-derived melanoma cell line B16F10 that ensures the production of tumors on mice pinnae that are similar in size between animals and that enlarge in a time-dependent manner. In this model, B16F10 cells are first allowed to develop tumors after injection in the interscapular area or flank of C57BL/6J mice. Subsequently, the tumors are harvested, cells dissociated and injected into mouse pinnae. Dose-dependent studies revealed that injection of 2 × 10⁵ cells allowed for slow tumor enlargement, producing tumors averaging 100 mm³ within 2 to 3 wk with a metastatic frequency of 100%. This experimental protocol will be useful in dissecting the immunobiology of melanoma tumor development and metastasis and the evaluation of immunotherapeutic antimelanoma therapies.

Cytomegalovirus (CMV) is a common chronic herpesvirus found in humans and numerous other mammalian species. In people, chronic viruses like CMV can alter overall health and immunity and pose a serious risk for those with an inadequate immune system. In addition, CMV plays an important role in animal health, and could affect the health of vulnerable populations, like endangered species. Previous studies found a high rate of CMV seropositivity among adult baboons (Papio anubis), and results from our laboratory revealed that baboon CMV (BaCMV) seropositivity was correlated with altered immune cell populations. In the current study, we further characterized BaCMV infection in normal, adult baboons. Analysis of blood samples from baboons (age, 6 to 26 y) revealed a low overall prevalence of detectable of BaCMV DNA, with a higher detection rate in aged baboons (older than 15 y). Furthermore, data suggest that individual baboons maintain similar rates of recurrence and levels of BaCMV shedding in saliva over time. Finally, we evaluated multiple commercially available assays for antihuman CMV IgG and IgM for use with baboon sera. Results of this study will improve our understanding of BaCMV and may be directly relevant to other closely related species.