Institutional training programs for research personnel conducted by laboratory-animal veterinarians.

Research institutions are required by federal law and national standards to ensure that individuals involved in animal research are appropriately trained in techniques and procedures used on animals. Meeting these requirements necessitates the support of institutional authorities; policies for the documentation and enforcement of training; resources to support and provide training programs; and high-quality, effective educational material. Because of their expertise, laboratory-animal veterinarians play an essential role in the design, implementation, and provision of educational programs for faculty, staff, and students in biomedical research. At large research institutions, provision of a training program for animal care and use personnel can be challenging because of the animal-research enterprise's size and scope. At the University of Michigan (UM), approximately 3,500 individuals have direct contact with animals used in research. We describe a comprehensive educational program for animal care and use personnel designed and provided by laboratory-animal veterinarians at UM and discuss the challenges associated with its implementation.

VIOLIN: vaccine investigation and online information network.

Vaccines are among the most efficacious and cost-effective tools for reducing morbidity and mortality caused by infectious diseases. The vaccine investigation and online information network (VIOLIN) is a web-based central resource, allowing easy curation, comparison and analysis of vaccine-related research data across various human pathogens (e.g. Haemophilus influenzae, human immunodeficiency virus (HIV) and Plasmodium falciparum) of medical importance and across humans, other natural hosts and laboratory animals. Vaccine-related peer-reviewed literature data have been downloaded into the database from PubMed and are searchable through various literature search programs. Vaccine data are also annotated, edited and submitted to the database through a web-based interactive system that integrates efficient computational literature mining and accurate manual curation. Curated information includes general microbial pathogenesis and host protective immunity, vaccine preparation and characteristics, stimulated host responses after vaccination and protection efficacy after challenge. Vaccine-related pathogen and host genes are also annotated and available for searching through customized BLAST programs. All VIOLIN data are available for download in an eXtensible Markup Language (XML)-based data exchange format. VIOLIN is expected to become a centralized source of vaccine information and to provide investigators in basic and clinical sciences with curated data and bioinformatics tools for vaccine research and development. VIOLIN is publicly available at http://www.violinet.org.

Pathobiology and management of laboratory rodents administered CDC category A agents.

The Centers for Disease Control and Prevention Category A infectious agents include Bacillus anthracis (anthrax), Clostridium botulinum toxin (botulism), Yersinia pestis (plague), variola major virus (smallpox), Francisella tularensis (tularemia), and the filoviruses and arenaviruses that induce viral hemorrhagic fevers. These agents are regarded as having the greatest potential for adverse impact on public health and therefore are a focus of renewed attention in infectious disease research. Frequently rodent models are used to study the pathobiology of these agents. Although much is known regarding naturally occurring infections in humans, less is documented on the sources of exposures and potential risks of infection to researchers and animal care personnel after the administration of these hazardous substances to laboratory animals. Failure to appropriately manage the animals can result both in the creation of workplace hazards if human exposures occur and in disruption of the research if unintended animal exposures occur. Here we review representative Category A agents, with a focus on comparing the biologic effects in naturally infected humans and rodent models and on considerations specific to the management of infected rodent subjects. The information reviewed for each agent has been curated manually and stored in a unique Internet-based database system called HazARD (Hazards in Animal Research Database, http://helab.bioinformatics.med.umich.edu/hazard/) that is designed to assist researchers, administrators, safety officials, Institutional Biosafety Committees, and veterinary personnel seeking information on the management of risks associated with animal studies involving hazardous substances.

Viral Vector Biosafety in Laboratory Animal Research.

Viral vector research presents unique occupational health and safety challenges to institutions due to the rapid development of both in vivo and in vitro gene-editing technologies. Risks to human and animal health make it incumbent on institutions to appropriately evaluate viral vector usage in research on the basis of available information and governmental regulations and guidelines. Here we review the factors related to risk assessment regarding viral vector usage in animals and the relevant regulatory documents associated with this research, and we highlight the most commonly used viral vectors in research today. This review is particularly focused on the background, use in research and associated health and environmental risks related to adenoviral, adeno-associated viral, lentiviral, and herpesviral vectors.

Renal transitional cell carcinoma and choristoma in a degu (Octodon degus).

A 4.5-year-old female degu (Octodon degus) was minimally responsive with a poor body condition, a rough haircoat, and moderate dehydration. Blood was present around its urethral orifice and on the cage bedding. Laboratory analyses revealed leukocytosis with neutrophilia and anemia; hypoproteinemia and hypoalbuminemia; hyperglycemia, hyperphosphatemia, and elevated alanine aminotransferase, blood urea nitrogen, and creatinine; and hematuria and pyuria with occasional squamous and transitional epithelial cells. A urine culture was positive for coagulase-negative Staphylococcus sp. On gross necropsy, the right kidney was enlarged, cystic, and greenish-brown, with a 10-mm, hemorrhagic, granular mass extending from the renal pelvis into the cranial cortex. Only a small amount of renal cortex appeared normal. The urinary bladder had focal areas of hemorrhage and contained frank blood. Histologically, the papillary mass in the right renal pelvis comprised basophilic, moderately anaplastic, clustered epithelial transition cells consistent with a transitional cell carcinoma. Internally, the tumor showed squamous metaplasia and moderate multifocal interstitial fibrosis. The right kidney cortex contained a choristoma comprising trabecular bone, mature adipocytes, and cellular infiltrates suggestive of osteocytes, lymphocytes, and plasma cells. The urinary bladder had mild to moderate, focal, hemorrhage with neutrophilic inflammation and contained focal areas of mild transitional cell epithelial hyperplasia; these changes may have been secondary to irritation by hemorrhage in the renal pelvis. There was no evidence of metastasis. Renal transitional cell tumors are rare in rodents. This is the first report of both a renal transitional cell carcinoma and a renal choristoma in a degu.

Ulcerative Dermatitis in C57BL/6NCrl Mice on a Low-Fat or High-Fat Diet With or Without a Mineralized Red-Algae Supplement.

Ulcerative dermatitis (UD) is a spontaneous idiopathic disease that often affects C57BL/6 mice or mice on a C57BL/6 background. UD is characterized by intense pruritus and lesion formation, most commonly on the head or dorsal thorax. Self-trauma likely contributes to wound severity and delayed wound healing. Histologically, changes are nonspecific, consisting of ulceration with neutrophilic and mastocytic infiltration and epithelial hyperplasia and hyperkeratosis. Diet appears to have a profound effect on the development and progression of UD lesions. We investigated the incidence and severity of UD in C57BL/6NCrl mice on a high-fat western-style diet (HFWD) compared with a standard rodent chow. In addition, we examined the protective effects of dietary supplementation with a multimineral-rich product derived from marine red algae on UD in these 2 diet groups. HFWD-fed mice had an increased incidence of UD. In addition, mice on a HFWD had significantly more severe clinical and histologic lesions. Dietary mineral supplementation in mice on a HFWD decreased the histologic severity of lesions and reduced the incidence of UD in female mice in both diets. In conclusion, a high-fat western-style diet may potentiate UD in C57BL/6NCrl mice. Insufficient mineral supply and mineral imbalance may contribute to disease development. Mineral supplementation may be beneficial in the treatment of UD.

Polycystic and chronic kidney disease in a young degu (Octodon degus).

A young adult (approximately 20 months), 125 g, female degu (Octodon degus) was housed with a male degu for approximately 1.2 years as a breeding pair. The female was multiparous and had weaned its third litter 2 weeks earlier. The degu was reported to the veterinary service for bloody vaginal discharge and a hunched, thin appearance of 1 day's duration. On physical examination, it exhibited cachexia, molting, slight matting of the hair around the eyes, and moderate dehydration. Hematology results included anemia and leukopenia with lymphocytopenia. Biochemical abnormalities included severe azotemia and phosphatemia. Urine specific gravity was 1.016. The condition of this animal prohibited its continued use in the breeding colony, so it was submitted for necropsy. On gross examination, the left kidney measured 10 x 15 mm, had an irregular surface, and was pale and mildly enlarged, consistent with compensatory hypertrophy. The right kidney was small (5 x 8 mm) and cystic. Both adrenal glands appeared mildly enlarged. Histologically, the left kidney had multiple regions with chronic, diffuse interstitial nephritis, and the right kidney was polycystic. There was mild, focal, cortical nodular hyperplasia in the adrenal glands. In the uterus, there was unilateral, locally extensive necrosis of the endometrium. The clinical chemistry results and histopathology findings are supportive of a diagnosis of renal failure secondary to chronic nephritis and polycystic kidney disease. The etiology of the nephritis is unknown. Polycystic kidney disease can be congenital or hereditary in other rodents.

Quantification of TNF-alpha and IL-6 bioactivity in response to lipopolysaccharide in the degu (Octodon degus).

The proinflammatory cytokines TNF-alpha and IL-6 are important inflammatory mediators that may be regulated by circadian rhythms. However, the production and detection of these cytokines have not been examined in the degu, a diurnal species used in some studies of circadian rhythms. In this study, we used bioassays to attempt to measure tumor necrosis factor (TNF-alpha) and interleukin 6 (IL-6) levels in degus exposed to an inflammatory stimulus, lipopolysaccharide (LPS). In an in vitro study, whole blood was incubated with LPS. After 6 and 24 h of LPS stimulation, TNF-alpha levels were substantially increased. However, IL-6 was not found in any of the samples. In an in vivo study, LPS was given to degus intraperitoneally. Similar to responses seen in other species, LPS stimulation resulted in marked neutrophil recruitment into the peritoneal space but not the alveolar space. TNF-alpha was present in large amounts in plasma and/or peritoneal lavage fluid. Again, IL-6 was not detectable with the bioassay. These findings suggest that degus do not produce IL-6, that they produce IL-6 in extremely small amounts, or that the bioassay is unable to detect IL-6 from degus. In conclusion, using well-established models of acute inflammation, this study demonstrated that TNF-alpha, but not IL-6, could be detected in plasma and peritoneal lavage fluids from degus with standard bioassays used for cytokine detection in other species.

Progression of ulcerative dermatitis lesions in C57BL/6Crl mice and the development of a scoring system for dermatitis lesions.

Ulcerative dermatitis (UD) is a common, spontaneous condition in mice with a C57BL/6 background. Although initial lesions may be mild, UD is a progressive disease that often results in ulcerations or debilitating fibrotic contractures. In addition, lesions typically are unresponsive to treatment. Euthanasia is often warranted in severe cases, thereby affecting study outcomes through the loss of research subjects. Because the clinical assessment of UD can be subjective, a quantitative scoring method and documentation of the likely time-frame of progression may be helpful in predicting when animals that develop dermatitis should be removed from a study. Such a system may also be helpful in quantitatively assessing success of various treatment strategies and be valuable to clinical laboratory animal veterinarians. In this 1.5-y, prospective cohort study, we followed 200 mice to monitor the development and course of UD. Mice were examined every 2 wk. A clinical sign (alopecia, pruritus, or peripheral lymphadenopathy) was not identified that predicted development of UD lesions in the subsequent 2-wk period. Once UD developed, pruritus, the character of the lesion (single or multiple crust, coalescing crust, erosion, or ulceration), and the size of the lesion were the only parameters that changed (increased) over the course of the disease. Pruritus was a factor in the rapid progression of UD lesions. We used these findings to develop a quantitative scoring system for the severity of UD. This enhanced understanding of the progression of UD and the quantitative scoring system will enhance the monitoring of UD.