Comparative medicine最新文献

Multiple animal models have been developed to investigate the pathogenesis of colorectal cancer and to evaluate potential treatments. One model system uses azoxymethane, a metabolite of cycasin, alone and in conjunction with dextran sodium sulfate to induce colon cancer in rodents. Azoxymethane is metabolized by hepatic P450 enzymes and can also be eliminated through the kidneys. In this study, C57BL/6J mice were fed either standard or high-fat diet and then all mice received azoxymethane at 10 mg/kg body weight twice a week for 6 wk. Shortly after the end of treatment, high mortality occurred in mice in the high-fat diet group. Postmortem examination revealed hepatic and renal pathology in mice on both diets. Histologic changes in liver included hepatocytomegaly with nuclear pleomorphism and bile duct hyperplasia accompanied by mixed inflammatory-cell infiltrates. Changes in the kidneys ranged from basophilia of tubular epithelium to tubular atrophy. The results indicate that further optimization of this model is needed when feeding a high-fat diet and giving multiple azoxymethane doses to induce colon cancer in C57BL/6J mice.

The ruminant alimentary tract and its effects on blood homeostasis complicate prolonged terminal studies conducted under general anesthesia in sheep. We therefore studied 15 healthy female white alpine sheep that were undergoing prolonged anesthesia (> 30 h) for an unrelated terminal study. In the current study, all sheep developed a decreased hematocrit and hemoglobin concentration after induction of anesthesia, which fell further, along with a significant decrease in white blood cell count, over the course of anesthesia. Sheep also showed an initial hyponatremia, a persistent hypokalemia, hypocalcemia, and a progressive hyperchloremia. A significant drop in blood pH developed over time despite normal values of blood lactate and a marked decline in partial pressure of carbon dioxide over the course of the experiment. The latter consequently reduced the efficacy of mechanical ventilation, as reflected in a reduced oxygen partial pressure. A significant increase in lactate dehydrogenase and creatinine kinase was observed. Arterial blood pressure and heart rate significantly decreased over time, but remained within normotensive and normocardic limits. Central venous pressure rose significantly over the course of anesthesia. In conclusion, prolonged anesthesia in sheep is associated with a wide range of complex physi- ologic changes. An in-depth understanding of all metabolic compensatory mechanisms and their underlying cause during prolonged anesthesia is necessary for interpreting data from the primary study, with special considerations to account for ruminant-specific physiology.

Klebsiella pneumoniae (Kp) is a gram-negative opportunistic pathogen that causes severe pneumonia, pyelonephritis, and sepsis in immunocompromised hosts. During a 4-mo interval, several NOD.Cg-Prkdc^scidIl2rg^tm1Wjl/SzJ (NSG) breeders and pups in our facilities were diagnosed with Kp infections. An initial 6 adult and 1 juvenile NSG mice were submitted for necropsy and histologic examination because of acute onset of diarrhea and death. The evaluation revealed typhlocolitis in 2 of the mice and tritrichomoniasis in all 7. Escherichia coli positive for polyketide synthase (pks+) and Kp were isolated from the intestines. Given a history of sepsis due to pks⁺ E. coli in NSG mice in our facilities and determination of its antimicrobial susceptibility, trimethoprim-sulfamethoxazole (TMP-SMX) was administered to the colony in the drinking water for 4 wk. After this intervention, an additional 21 mice became ill or died; 11 of these mice had suppurative pneumonia, meningoencephalitis, hepatitis, metritis, pyelonephritis, or sepsis. Kp was cultured from pulmonary abscesses or blood of 10 of the mice. Whole-genome sequencing (WGS) indicated that the Kp isolates contained genes associated with phenotypes found in pore-forming Kp isolates cultured from humans with ulcerative colitis and primary sclerosing cholangitis. None of the Kp isolates exhibited a hyperviscous phenotype, but 13 of 14 were resistant to TMP-SMX. Antimicrobial susceptibility testing indicated sensitivity of the Kp to enrofloxacin, which was administered in the drinking water. Antibiotic sensitivity profiles were confirmed by WGS of the Kp strains; key virulence and resistance genes to quaternary ammonia compounds were also identified. Enrofloxacin treatment resulted in a marked reduction in mortality, and the study using the NSG mice was completed successfully. Our findings implicate intestinal translocation of Kp as the cause of pneumonia and systemic infections in NSG mice and highlight the importance of identification of enteric microbial pathogens and targeted antibiotic selection when treating bacterial infections in immunocompromised mice.

A 3-y-old male pigtailed macaque (Macaca nemestrina) presented for swelling of the left distal forearm and decreased use of the arm. The monkey had been raised at an indoor-outdoor facility in Arizona and transferred to an indoor facility in Washington 2 mo prior to presentation. A preliminary diagnosis of fungal osteomyelitis of the radius was made based on radiographs and Coccidioides titers. In addition to systemic antifungal treatment, surgery was performed to debride the bony lesion and implant polymethylmethacrylate beads impregnanted with the anti-fungal fluconazole. Histologic examination of the debrided material confirmed the diagnosis of fungal osteomyelitis. The surgical procedure resulted in clinical improvement, as evidenced by weight gain and decreased Coccidioides titers. The beads were removed in a second surgery, and the bony lesion completely resolved. With continued systemic fluconazole treatment, the monkey remained healthy with no further evidence of osteomyelitis. Coccidioides is an emerging pathogen that causes significant morbidity and mortality in both humans and animals. Bone infections can be resistant to systemic treatment, and the implantation of fluconazoleimpregnated beads may offer a successful treatment strategy for fungal osteomyelitis.

This report describes an anesthesia technique that we used to study cardiovascular anatomy and physiology with echocardiography and cardiac magnetic resonance (CMR) in 46 African clawed frogs (Xenopus laevis) (n = 24 for electrocardiography and n = 22 for CMR). For administration of anesthesia, 3 holding tanks, one each for transportation, sedation, and recovery, were filled with filtered water, with 0.05% buffered tricaine methasulfonate solution (MS-222) added into the sedation tank. Fifteen minutes after the frog was placed in the sedation tank, a paper towel was soaked in MS-222 solution, and the frog was placed in a supine position and rolled 3 to 4 times in the soaked paper with the head and legs exposed. Vital signs were monitored and recorded throughout the procedure. After imagining, frogs were unrolled from the paper towel, placed in the recovery tank, and later returned to their home tank. Monitoring was discontinued when the frogs resumed typical activity. No mortality or complications were observed in frogs that underwent this procedure. Mean duration ±1 SD of anesthesia induction was 12 ± 5 min in the echocardiography group and 14 ± 6 min in the CMR group. The mean duration of anesthesia maintenance was 60 ± 18 min in the echocardiography group and 118 ± 37 min in the CMR group. An additional dose of anesthesia was necessary during maintenance for 9 of 24 (37%) frogs in the echocardiography group and 6 of 22 (27%) frogs in the CMR group. At the end of the procedure, the mean oxygen saturation was 66 ± 9% in the echocardiography group and 85 ± 6% in the CMR group, and heart rate was 48 ± 13 beats/min in the echocardiography group and 42 ± 7 beats/min in the CMR group. We conclude that the anesthesia technique of immersion in MS-222 is suitable for performing echocardiography and CMR imaging in this species without complications.

Plethysmography is used in nonhuman primates (NHPs) to measure minute volume before aerosol exposure to an agent to calculate total time necessary in the exposure chamber. The consistency of respiratory parameters during the entire exposure time is paramount to ensuring dosing accuracy. Our study sought to validate an alfaxalone-midazolam (AM) anesthetic combination for use in aerosol studies. We hypothesized that AM would provide an adequate duration of anesthesia, achieve and maintain steady state minute volume (SSMV) for 20 min, and have anesthetic quality and side effects comparable to or better than either tiletamine-zolazepam (TZ) and ketamine-acepromazine (KA), the most common anesthetics used for this purpose currently. Two groups of NHPs, one consisting of 15 cynomolgus macaques and one of 15 rhesus macaques, received 3 intramuscular anesthetic combinations (AM, TZ, and KA), no less than one week apart. Anesthetized NHPs were placed in a plethysmograph chamber and their minute volumes were measured every 10 s to determine whether they had achieved SSMV and maintained it for at least 20 consecutive min. Achieving and reliably maintaining an SSMV for at least 20 min facilitates precise aerosol dosing of a challenge agent. Quality of anesthesia, based on the NHP's ability to achieve and maintain SSMV, was higher with AM compared with TZ and KA in both species, and AM had a longer duration of SSMV as compared with TZ and KA in cynomolgus macaques. Average SSMV was larger with AM compared with TZ in cynomolgus macaques, but larger with KA compared with AM in rhesus macaques. Duration of anesthesia was sufficient with all combinations but was longer for TZ than both AM and KA in both species. These results suggest that the AM anesthetic combination would produce the most accurate dosing for an aerosol challenge.

Fenbendazole remains the drug of choice to treat pinworm infection in laboratory rodents. When fenbendazole was last reviewed (15 y ago), the literature supported the drug's lack of toxic effects at therapeutic levels, yet various demonstrated physiologic effects have the potential to alter research outcomes. Although more recent reports continue to reflect an overall discordancy of results, several studies support the premise that fenbendazole affects the bone marrow and the immune system. No effects on reproduction were reported in an extensive study that assessed common treatment protocols in mice, and food intake was unchanged in rats. Behavioral studies are sparse, with only a single report of a subtle change in a rotarod performance in mice. Notably, unexpected results in tumor models during facility treatment with fenbendazole have prompted preclinical and clinical studies of the potential roles of benzimidazoles in cancer.

Chlamydia muridarum (Cm) was detected in 2 colonies of mice with lymphoplasmacytic pulmonary infiltrates by using PCR and immunohistochemistry. This discovery was unexpected, as Cm infection had not been reported in laboratory mice since the 1940s. A Cm specific PCR assay was developed and testing implemented for the resident colonies of 8 vivaria from 3 academic institutions, 58 incoming mouse shipments from 39 academic institutions, and mice received from 55 commercial breeding colonies (4 vendors). To estimate Cm's global prevalence in research colonies, a database containing 11,387 metagenomic fecal microbiota samples from 120 institutions and a cohort of 900 diagnostic samples from 96 institutions were examined. Results indicate significant prevalence among academic institutions, with Cm detected in 63% of soiled bedding sentinels from 3 institutions; 33% of incoming mouse shipments from 39 academic institutions; 14% of 120 institutions submitting microbiota samples; and 16% of the diagnostic sample cohort. All samples from commercial breeding colonies were negative. In addition, naïve NOD. Cg-Prkdc^scidIl2rg^tm1Wjl/SzJ (NSG) mice exposed to Cm-shedding mice and/or their soiled bedding developed clinical disease at 21 to 28 d after exposure. These mice had a moderate-to-severe histiocytic and neutro- philic bronchointerstitial pneumonia, with their respiratory epithelium demonstrating inclusions, chlamydial major outer membrane protein immunostaining, and hybridization with a Cm reference sequence (GenBank accession no. U68436). Cm was isolated from lungs, cecum, and feces of a Cm-infected NSG mouse by using HeLa 229 cells. The considerable prevalence of Cm is likely due to widespread global interinstitutional distribution of unique mouse strains and failure to recognize that some of these mice were from enzootically infected colonies. Given that experimental Cm colonization of mice results in a robust immune response and, on occasion, pathology, natural infection may confound experimental results. Therefore, Cm should be excluded and eradicated from enzootically infected mouse colonies.

Age-associated neurodegenerative changes, including amyloid β (Aβ) plaques, neurofibrillary tangles (NFTs), and amyloid angiopathy comparable to those seen in the brains of human patients with Alzheimer's disease (AD), have been reported in the brains of aged bears. However, the significance of these findings in bears is unclear due to the difficulty in assessing cognitive impairment and the lack of standardized approaches for the semiquantitative evaluation of Aβ plaques and NFTs. In this study, we evaluate the neuropathologic changes in archival brain tissue of 2 aged polar bears (Ursus maritimus, ages 28 and 37) using the National Institute of Aging-Alzheimer Association (NIA-AA) consensus guidelines for the neuropathologic assessment of Alzheimer's Disease (AD). Both bears had an Aβ (A) score of 3 of 3, Braak stage (B score) of 2 of 3, and neuritic plaque (C) score of 3 of 3. These findings are consistent with the neurodegenerative changes observed in brains of patients with AD. The application of NIA-AA consensus guidelines, as applied to the neuropathologic assessment of the aged bears in this report, demonstrates the use of standardized semiquantitative assessment systems for comparative, translational studies of aging in a vulnerable wildlife species.