According to the Guide, cage change frequencies must be considered when cage density requirements are exceeded. We monitored ammonia, carbon dioxide, cage wetness, health status, and breeding parameters of trio and pair breeding cages containing CD1 mice in ventilated and static microisolation caging (4 cages per condition) daily for approximately 6 wk. Minimum cage change frequencies for each condition were determined on the basis of performance data. At 3 d after cage change, static trio and pair cages had average ammonia levels of 74 and 38 ppm. Ventilated cages remained below the 25ppm threshold reported to be potentially deleterious for mice until at least day 7 after cage change. By 7 d after cage change, ammonia levels had risen to an average of 100 ppm and 64 ppm in static trio and pair cages and to 34 ppm and 20 ppm in ventilated trio and pair cages, respectively. Ammonia levels in ventilated cages continued to rise slowly through day 14 after cage change. CO2 levels exceeded 5000 ppm in all groups at 2 d after cage change. Pair breeders in ventilated cages took the longest—10 to 14 d—to reach cage wetness threshold scores. On day 7, pups in trio static cages were noted to have decreased and squinted eyes, whereas in ventilated cages containing trios and pairs, these clinical signs were rare to absent. Histologically, there was an increasing incidence and severity of nasal lesions in weanlings with increasing housing density and decreasing ventilation, consistent with nasal epithelial toxicity. Given these parameters, we concluded that under the current husbandry conditions, it may be necessary to change breeders in static cages more frequently than every 7 d. Additional studies are necessary to evaluate the effects of more frequent cage changes on reproductive parameters, given that cage changing is stressful for mice and affects breeding results.
Sepsis is a multifaceted host response to infection that dramatically affects patient outcomes and the cost of health care. Animal models are necessary to replicate the complexity and heterogeneity of clinical sepsis. However, these models entail a high risk of pain and distress due to tissue trauma, inflammation, endotoxin-mediated hyperalgesia, and other mechanisms. Several recent studies and initiatives address the need to improve the welfare of animals through analgesics and standardize the models used in preclinical sepsis research. Ultimately, the goal is to provide high-fidelity, humane animal models that better replicate the clinical course of sepsis, to provide more effective translation and advance therapeutic discovery. The purpose of this review is to discuss the current understanding of the roles of pain and analgesia in rodent models of sepsis. The current definitions of sepsis along with an overview of pain in human sepsis are described. Finally, welfare concerns associated with animal models of sepsis and the most recent considerations for relief of pain and distress are reviewed.
Regulatory guidelines mandate housing for laboratory mice at temperatures below their thermoneutral zone, creating chronic cold stress. However, increases in housing temperature could alter immune responses. We hypothesized housing mice at temperatures within their thermoneutral zone would improve sepsis survival and alter immune responses. Male C57BL/6 mice were housed at 22°C or 30°C after cecal ligation and puncture (CLP) for 10 days. Survival of mice housed at 30°C (78%) after CLP was significantly increased compared with mice housed at 22°C (40%). Experimental groups were repeated with mice euthanized at 0, 12, 24, and 48 h post-surgery to examine select immune parameters. Raising housing temperature minimally altered systemic, peritoneal, or splenic cell counts. However, IL-6 levels in plasma and peritoneal lavage fluid were significantly lower at 12 h post-surgery in mice housed at 30°C compared with 22°C. Bacterial colony counts from peritoneal lavage fluid were significantly lower in mice housed at 30°C and in vivo studies suggested this was the result of increased phagocytosis by neutrophils. As previously demonstrated, adoptive transfer of fibrocytes significantly increased sepsis survival compared with saline at 22°C. However, there was no additive effect when adoptive transfer was performed at 30°C. Overall, the results demonstrated that thermoneutral housing improves survival after CLP by increasing local phagocytic activity and technical revisions may be necessary to standardize the severity of the model across different housing temperatures. These findings stress the pronounced impact housing temperature has on the CLP model and the importance of reporting housing temperature.
Severe subglottic stenosis develops in over 20,000 infants per year and requires laryngotracheal reconstruction (LTR) to enlarge the airway by implanting autologous cartilage from a rib graft. However, young children often lack sufficiently sized costal cartilage resulting in increased donor site morbidity and operative time, as well as an elevated risk for airway restenosis necessitating revision surgery. To overcome these limitations, we have created a first-of-its-kind scaffold based on porcine meniscal cartilage decellularization (MEND) by selectively digesting the elastin and blood vessels uniquely present in the meniscus to create microchannels that support cellular re-invasion. Here we demonstrated that MEND can be fully recellularized in 3 days with ear-derived cartilage progenitor cells (eCPCs) and reaches structural and functional maturation suitable for implant within 3 weeks of chondrogenic differentiation, a time frame compatible with clinical translation, a first in airway tissue engineering. To further this therapy toward clinical translation, we validated the eCPCs-MEND grafts in a New Zealand white rabbit LTR model. Our results demonstrated airway expansion, graft re-epitheliazation, neocartilage formation, and integration with adjacent native laryngotracheal cartilage, notably at a higher degree than the standard of care of autologous costal cartilage. No instances of adverse events of extrusion, granulation, infection, or calcification were observed in any of the 38 rabbits of our 3 months study. These results demonstrate the feasibility of our translational tissue engineering approach to laryngotracheal reconstruction and could overcome the autograft-associated limitations in pediatric patients and a decrease the risk of invasive revision surgery.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the worldwide coronavirus (COVID-19) pandemic, has infected an estimated 525 million people with over 6 million deaths. Although COVID-19 is primarily a respiratory disease, an escalating number of neurologic symptoms have been reported in humans. Some neurologic symptoms, such as loss of smell or taste, are mild. However, other symptoms, such as meningoencephalitis or stroke, are potentially fatal. Along with surveys and postmortem evaluations on humans, scientists worked with several animal species to try to elucidate the causes of neurologic symptoms. Neurologic sequelae remain challenging to study due to the complexity of the nervous system and difficulties in identification and quantification of neurologic signs. We reviewed animal models used in the study of neurologic COVID-19, specifically research in mice, hamsters, ferrets, and nonhuman primates. We summarized findings on the presence and pathologic effects of SARS-CoV-2 on the nervous system. Given the need to increase understanding of COVID-19 and its effects on the nervous system, scientists must strive to obtain new information from animals to reduce mortality and morbidity with neurologic complications in humans.
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