Comparative medicine最新文献

C57BL/6J (B6) mice are commonly affected by ulcerative dermatitis (UD), a disease of unknown etiology with poor response to treatment. To study the possible role of diet in UD, we compared skin changes in B6 female mice fed a high-fat diet with those of mice fed a control diet. In addition, skin samples from mice with no, mild, moderate, and severe clinical signs of UD were examined by light and transmission electron microscopy (TEM). Mice fed a high-fat diet for 2 mo had more skin mast cell degranulation than did mice fed the control diet for the same period. Regardless of diet, older mice had more skin mast cells and more of these cells were degranulating as compared with younger mice. Microscopic changes in very early lesions were characterized by an increase in dermal mast cells and degranulation with focal areas of epidermal hyperplasia with or without hyperkeratosis. As the condition progressed, a mixed but predominantly neutrophilic inflammatory cell infiltrate appeared in the dermis, with or without epidermal erosion and scab formation. TEM showed that dermal mast cell membranes had disrupted and released of large number of electron dense granules, whereas degranulated mast cells were filled with isolated and coalescing empty spaces due to fusion of granule membranes. Ulceration appeared to occur very quickly, probably as result of intense scratching due to the pruritogenic properties of the histamine released from mast cell granules. This study showed a direct correlation between dietary fat and skin mast cell degranulation in female B6 mice. In addition, the number of skin mast cells and degranulation rates was higher in older mice. Treatments directed at preventing mast cell degranulation may result in better outcomes when applied early in UD cases. As noted previously in studies using caloric restriction, lower fat content in rodent diets may help prevent UD.

Emergence of the betacoronavirus SARS-CoV-2 has resulted in a historic pandemic, with millions of deaths worldwide. An unprecedented effort has been made by the medical, scientific, and public health communities to rapidly develop and implement vaccines and therapeutics to prevent and reduce hospitalizations and deaths. Although SARS-CoV-2 infection can lead to disease in many organ systems, the respiratory system is its main target, with pneumonia and acute respiratory distress syndrome as the hallmark features of severe disease. The large number of patients who have contracted COVID-19 infections since 2019 has permitted a detailed characterization of the clinical and pathologic features of the disease in humans. However, continued progress in the development of effective preventatives and therapies requires a deeper understanding of the pathogenesis of infection. Studies using animal models are necessary to complement in vitro findings and human clinical data. Multiple animal species have been evaluated as potential models for studying the respiratory disease caused by SARSCoV-2 infection. Knowing the similarities and differences between animal and human responses to infection is critical for effective translation of animal data into human medicine. This review provides a detailed summary of the respiratory disease and associated pathology induced by SARS-CoV-2 infection in humans and compares them with the disease that develops in 3 commonly used models: NHP, hamsters, and mice. The effective use of animals to study SARS-CoV-2-induced respiratory disease will enhance our understanding of SARS-CoV-2 pathogenesis, allow the development of novel preventatives and therapeutics, and aid in the preparation for the next emerging virus with pandemic potential.

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.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as the viral pathogen that led to the global COVID-19 pandemic that began in late 2019. Because SARS-CoV-2 primarily causes a respiratory disease, much research conducted to date has focused on the respiratory system. However, SARS-CoV-2 infection also affects other organ systems, including the cardiovascular system. In this critical analysis of published data, we evaluate the evidence of cardiovascular pathology in human patients and animals. Overall, we find that the presence or absence of cardiovascular pathology is reported infrequently in both human autopsy studies and animal models of SARS-CoV-2 infection. Moreover, in those studies that have reported cardiovascular pathology, we identified issues in their design and execution that reduce confidence in the conclusions regarding SARS-CoV-2 infection as a cause of significant cardiovascular pathology. Throughout this overview, we expand on these limitations and provide recommendations to ensure a high level of scientific rigor and reproducibility.

The existence of coronaviruses has been known for many years. These viruses cause significant disease that primarily seems to affect agricultural species. Human coronavirus disease due to the 2002 outbreak of Severe Acute Respiratory Syndrome and the 2012 outbreak of Middle East Respiratory Syndrome made headlines; however, these outbreaks were controlled, and public concern quickly faded. This complacency ended in late 2019 when alarms were raised about a mysterious virus responsible for numerous illnesses and deaths in China. As we now know, this novel disease called Coronavirus Disease 2019 (COVID-19) was caused by Severe acute respiratory syndrome-related-coronavirus-2 (SARS-CoV-2) and rapidly became a worldwide pandemic. Luckily, decades of research into animal coronaviruses hastened our understanding of the genetics, structure, transmission, and pathogenesis of these viruses. Coronaviruses infect a wide range of wild and domestic animals, with significant economic impact in several agricultural species. Their large genome, low dependency on host cellular proteins, and frequent recombination allow coronaviruses to successfully cross species barriers and adapt to different hosts including humans. The study of the animal diseases provides an understanding of the virus biology and pathogenesis and has assisted in the rapid development of the SARS-CoV-2 vaccines. Here, we briefly review the classification, origin, etiology, transmission mechanisms, pathogenesis, clinical signs, diagnosis, treatment, and prevention strategies, including available vaccines, for coronaviruses that affect domestic, farm, laboratory, and wild animal species. We also briefly describe the coronaviruses that affect humans. Expanding our knowledge of this complex group of viruses will better prepare us to design strategies to prevent and/or minimize the impact of future coronavirus outbreaks.

The study of nonhuman primates (NHP) can provide significant insights into our understanding numerous infectious agents. The etiological agent of COVID-19, SARS-CoV-2 virus, first emerged in 2019 and has so far been responsible for the deaths of over 4 million people globally. In the frenzied search to understand its pathogenesis and immunology and to find measures for prevention and control of this pandemic disease, NHP, particularly macaques, are the preferred model because they manifest similar clinical signs and immunologic features as humans. However, possible latent, subclinical, and opportunistic infections not previously detected in animals participating in a study may obscure experimental results and confound data interpretations in testing treatments and vaccine studies for COVID-19. Certain pathophysiologic changes that occur with SARS-CoV-2 virus infection are similar to those of simian pathogens. The current review discusses numerous coinfections of COVID-19 with other diseases and describes possible outcomes and mechanisms in COVID-19 studies of NHP that have coinfections. Due to the urgency triggered by the pandemic, screening that is more rigorous than usual is necessary to limit background noise and maximize the reliability of data from NHP COVID-19 studies. Screening for influenza virus, selected respiratory bacteria, and regional endemic pathogens such as vector-borne agents, together with the animal's individual exposure history, should be the main considerations in selecting a NHP for a COVID-19 study. In addition, because NHP are susceptible to the SARS-CoV-2 virus, management and surveillance measures should be established to prevent transmission to healthy animals from infected colony animals and husbandry staff. This review presents compiled data on the use of NHP in COVID-19 studies, emphasizing the need to create the most reliable NHP model for those studies by extensive screening for other pathogens.

A Cancer Rainbow mouse line that expresses 3 fluorescently labeled isoforms of the tumor-driver gene HER2 (HER2BOW) was developed recently for the study of tumorigenesis in the mammary gland. The expression of 1 of the 3 HER2 isoforms in HER2BOW mice is induced through the Cre/lox system. However, in addition to developing palpable mammary tumors, HER2BOW mice developed orbital tumors, specifically of the Harderian gland. Mice were euthanized, and histopathologic examination of the Harderian gland tumors was performed. Tumors were characterized by adenomatous hyperplasia to multinodular adenomas of the Harderian gland. Fluorescent imaging of the Harderian gland tissue confirmed the expression of HER2 in the tumors. Here we discuss monitoring and palliative approaches to allow attainment of humane experimental endpoints of mammary tumor growth in this mouse line. We describe a range of interventions, including close monitoring, topical palliative care, and surgical bilateral enucleation. Based on our data and previous reports in the literature, the overexpression of HER2 in Harderian gland tissue and subsequent tumor formation likely was driven by MMTV-Cre expression in the Harderian gland.

Mouse kidney parvovirus (MKPV), the etiology of murine inclusion body nephropathy, has been identified globally in mice used for research, with an estimated prevalence of 10% in academic colonies. In immunodeficient strains, MKPV causes significant morbidity and mortality, and severe renal pathology. In contrast, in immunocompetent mice, the infection is subclinical and causes minimal pathology. We investigated viral infectivity and shedding in inbred C57BL/6NCrl (B6), outbred Crl:CD1(ICR) (CD1), and highly immunocompromised NOD. Cg - Prkdc scid Il2rg tm1Wjl/SzJ (NSG) mice. Four doses, ranging from 1.16 × 10 3 to 1.16 × 10 6 viral copies per microliter, of an MKPV inoculum were administered oronasally to 3 mice per dose per mouse type. All 3 types (B6, CD1, and NSG) had persistent infection with prolonged shedding in urine and feces. Viral copy number in the urine generally increased over time, while shedding in the feces was more variable. Among the 3 populations, CD1 mice developed viral shedding in urine earliest (4 wk after inoculation) and at higher levels (greater than 1 × 10 7 viral copies per microliter). B6 mice become viruric later (7 wk after inoculation), with lesser virus shed (1 × 10 6 viral copies per microliter or less). In CD1 and B6 mice, peak urine shedding occurred at 11 to 14 wk after inoculation, after which levels gradually declined until 35 wk after inoculation (study endpoint). In contrast, NSG mice did not become viruric until 10 wk after inoculation and continued to shed large amounts of virus (greater than 1 × 10⁷ viral copies per microliter) in urine until the study endpoint. Two commercial immunofluorescent serologic assays failed to detect serum antibodies to MKPV nonstructural protein 1 as late as 58 wk after inoculation, whereas immunohistochemistry of infected renal tissue successfully detected anti-MKPV serum antibodies. These results increase our knowledge of the biology of MKPV and have practical application for development of effective screening programs for this pathogen.

Repeatable tumor measurements are key to accurately assessing tumor growth and treatment efficacy. A preliminary study that we conducted showed that a novel 3D and thermal imaging system (3D-TI) for measuring subcutaneous tumors in rodents significantly reduced interoperator variability across 3 in vivo efficacy studies. Here we further studied this reduction in interoperator variability across a much larger dataset. A dataset consisting of 6,532 paired 3D-TI and caliper interoperator measurements was obtained from tumor scans and measurements in 27 laboratories across 289 studies, 153 operators, over 20 mouse strains, and 100 cell lines. Interoperator variability in both measurement methods was analyzed using coefficient of variation (CV), intraclass correlation (ICC) analysis, and significance testing. The median 3D-TI CV was significantly lower than the median caliper CV. The effects of large interoperator variability at critical points in the study were also investigated. At stratified randomization, changing the operator performing caliper measurements resulted in a 59% probability that a mouse would be reassigned to a different group. The probability that this would occur when using 3D-TI was significantly lower at 29%. In studies in which a tumor was expected to regress, changing the operator during the study was associated with a tumor volume increase of approximately 500mm³ when using calipers. This change did not occur when using 3D-TI. We conclude that 3D-TI significantly reduces interoperator variability as compared with calipers and can improve reproducibility of in vivo studies across a wide range of mouse strains and cell lines.