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Establishing the Median Infectious Dose and Characterizing the Clinical Manifestations of Mouse, Rat, Cow, and Human Corynebacterium bovis Isolates in Select Immunocompromised Mouse Strains. 建立小鼠、大鼠、牛和人牛棒状杆菌分离株免疫功能低下小鼠株的中位感染剂量和临床表现表征
IF 0.8 4区 农林科学 Q2 VETERINARY SCIENCES Pub Date : 2023-06-01 DOI: 10.30802/AALAS-CM-22-000115
Gerardo Mendoza, Christopher Cheleuitte-Nieves, Kvin Lertpiriyapong, Juliette Rk Wipf, Rodolfo Ricart J Arbona, Ileana C Miranda, Neil S Lipman

Corynebacterium bovis (Cb), the cause of hyperkeratotic dermatitis in various immunocompromised mouse strains, significantly impacts research outcomes if infected mice are used. Although Cb has been isolated from a variety of species, including mice, rats, cows, and humans, little is known about the differences in the infectivity and clinical disease that are associated with specific Cb isolates. The infectious dose that colonized 50% of the exposed population (ID50 ) and any associated clinical disease was determined in athymic nude mice (Hsd:Athymic Nude-Foxn1 nu ) inoculated with Cb isolates collected from mice (n = 5), rat (n = 1), cow (n = 1), and humans (n = 2) The same parameters were also determined for 2 of the mouse isolates in 2 furred immunocompromised mouse strains (NSG [NOD. Cg-Prkdcscid Il2rgtm1Wjl /Sz] and NSG-S [NOD. Cg-Prkdcscid Il2rgtm1Wjl Tg(CMV-IL3, CSF2, KITLG)1Eav/MloySzJ]). To determine the ID 50, mice (n= 6/dose; 3 of each sex) were inoculated topically in 10-fold increments ranging from 1 to 10 8 bacteria. Mice were scored daily for 14 days for the severity of clinical signs. On days 7 and 14 after inoculation, buccal and dorsal skin swabs were evaluated by aerobic culture to determine infection status. The mouse isolates yielded lower ID50values (58 to 1000 bacteria) than did the bovine (6460 to 7498 bacteria) and rat (10,000 bacteria) isolates. Human isolates did not colonize mice or cause disease. Mouse isolates produced clinical disease of vary- ing severity in nude mice. Despite significant immunodeficiency, furred NSG and NSG-S mice required a 1000- to 3000-fold higher inoculum for colonization than did athymic nude mice. Once colonized, clinically detectable hyperkeratosis did not develop in the haired strains until 18 to 22 d after inoculation, whereas athymic nude mice that developed clinically detect- able disease showed hyperkeratosis between 6 and 14 d after inoculation. In conclusion, there are significant differences in Cb's ID 50, disease course, and severity of clinical signs between Cb isolates and among immunodeficient mouse strains.

牛棒状杆菌(Cb)是各种免疫功能低下的小鼠品系中过度角化性皮炎的病因,如果使用受感染的小鼠,它会显著影响研究结果。虽然已从多种物种(包括小鼠、大鼠、奶牛和人类)中分离出梭状芽孢杆菌,但对与特定梭状芽孢杆菌分离物相关的传染性和临床疾病差异知之甚少。用从小鼠(n = 5)、大鼠(n = 1)、牛(n = 1)和人(n = 2)中收集的Cb分离株接种胸腺裸小鼠(Hsd: athymic nude - foxn1 nu),测定50%暴露人群(ID50)的感染剂量和任何相关临床疾病。2个毛免疫功能减退小鼠株(NSG [NOD])中的2个小鼠分离株也测定了相同的参数。g- prkdcscid Il2rgtm1Wjl /Sz]和NSG-S [NOD]。Cg-Prkdcscid il2rgtm1wj1tg (CMV-IL3, CSF2, KITLG)1Eav/MloySzJ))。小鼠(n= 6只/剂;每种性别各3只),以10倍的增量局部接种1至108个细菌。连续14天每天对小鼠进行临床症状严重程度评分。接种后第7天和第14天,用好氧培养法评估口腔和背部皮肤拭子的感染情况。小鼠分离株的id50值(58 ~ 1000个细菌)低于牛分离株(6460 ~ 7498个细菌)和大鼠分离株(10000个细菌)。人类分离株不会在小鼠体内定植或引起疾病。小鼠分离株在裸鼠身上产生不同程度的临床疾病。尽管有明显的免疫缺陷,毛毛NSG和NSG- s小鼠需要比胸腺裸鼠高1000至3000倍的接种量来定植。一旦定植,在接种后18至22天,毛株才出现临床可检测的角化过度,而发生临床可检测疾病的胸腺裸鼠在接种后6至14天出现角化过度。综上所述,在Cb分离株和免疫缺陷小鼠株之间,Cb的id50、病程和临床症状的严重程度存在显著差异。
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引用次数: 0
Spontaneous Vitiligo in a Captive Rhesus Monkey (Macaca Mulatta). 圈养猕猴(Macaca Mulatta)的自发性白癜风。
IF 0.8 4区 农林科学 Q2 VETERINARY SCIENCES Pub Date : 2023-06-01 DOI: 10.30802/AALAS-CM-22-000091
Bárbara Cs Meireles, Beatriz Goldschmidt, Cláudia A Lopes, Kelly C Demarque, Gabriel M Leal, Mariana S Magalhães, Milena B Souza, Ricardo S Cruz

Vitiligo affects a significant portion of human and animal populations. The disease causes irregular and multifocal progressive loss of fur, skin, and mucous membrane pigmentation due to the loss or absence of melanocytes. While etiopathogenesis is not completely understood, autoimmunity, environmental, and genetic factors are implicated We present a case report on a 16-y-old female rhesus macaque (Macaca mulatta ) with depigmented areas that are progressively increasing on the skin and coat and are distributed on the head and back. Histopathology revealed alterations compatible with vitiligo characterized by the absence of melanocytes in the epidermis and dermis. The clinical history and complementary exams support this diagnosis.

白癜风影响着人类和动物种群的很大一部分。由于黑色素细胞的丢失或缺失,该疾病导致毛皮、皮肤和粘膜色素沉着的不规则和多灶性进行性丧失。虽然病因尚不完全清楚,但涉及自身免疫、环境和遗传因素。我们报告了一例16岁雌性恒河猴(Macaca mulatta)的病例报告,其皮肤和皮毛上的色素脱色区域逐渐增加,并分布在头部和背部。组织病理学显示与白癜风相一致的改变,其特征是表皮和真皮中缺乏黑色素细胞。临床病史和辅助检查支持这一诊断。
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引用次数: 0
Ferrets as Models for Viral Respiratory Disease. 雪貂是病毒性呼吸道疾病的模型。
IF 0.8 4区 农林科学 Q2 VETERINARY SCIENCES Pub Date : 2023-06-01 Epub Date: 2023-05-31 DOI: 10.30802/AALAS-CM-22-000064
Rachel E Smith, Shambhunath Choudhary, Julita A Ramirez

Domestic ferrets (Mustela putorius furo) have been used in biomedical research to study influenza viruses since the early 20th century. Ferrets have continued to gain importance for the study of viral respiratory disease due to their disease susceptibility and anatomic similarities to humans. Here we review features of ferret biology and management that should be considered when planning to work with this species, particularly in models of respiratory disease. We specifically discuss biosafety and husbandry, clinical and pathologic assessments, and anesthetic considerations for ferrets with respiratory disease and systemic illness. These considerations are important for animal welfare, fidelity of the model to human disease, and ensuring accuracy and reproducibility of acquired data. Finally, we briefly review the use of ferrets to study respiratory diseases by discussing their respiratory anatomy and 2 frequently studied viral respiratory diseases, influenza and coronavirus disease 2019 (COVID-19).

自20世纪初以来,家养雪貂(Mustela putorius furo)已被用于生物医学研究,以研究流感病毒。由于雪貂的疾病易感性和与人类的解剖相似性,它们在病毒性呼吸道疾病的研究中一直具有重要意义。在这里,我们回顾了雪貂生物学和管理的特点,当计划与这个物种一起工作时,应该考虑到这一点,特别是在呼吸道疾病的模型中。我们特别讨论生物安全和饲养,临床和病理评估,以及麻醉考虑与呼吸系统疾病和全身疾病的雪貂。这些考虑对于动物福利、模型对人类疾病的保真度以及确保获得的数据的准确性和可重复性都很重要。最后,我们通过讨论雪貂的呼吸解剖以及2种经常被研究的病毒性呼吸道疾病,流感和冠状病毒病2019 (COVID-19),简要回顾了雪貂在呼吸道疾病研究中的应用。
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引用次数: 0
Severe Anemia in Sprague-Dawley Rats After Roux-en-Y Gastric Bypass Surgery. Roux-en-Y胃旁路手术后Sprague-Dawley大鼠的严重贫血。
IF 0.8 4区 农林科学 Q2 VETERINARY SCIENCES Pub Date : 2023-06-01 Epub Date: 2023-05-31 DOI: 10.30802/AALAS-CM-22-000074
Rachel L Griffin, Ashley N Varley, Andras Hajnal, Jennifer L Booth

Roux-en-Y gastric bypass (RYGB) surgery is one of the most commonly performed bariatric procedures for weight loss in humans. However, this procedure is not risk-free, and patients may experience complications that include small bowel obstruction, gastrointestinal bleeding, chronic diarrhea, ulcers, malnutrition, and anemia. In particular, anemia is a recognized long-term complication and can be severe. Rats have been used as a model to study the effects of gastric bypass surgeries. They can experience similar complications as people, but the development of severe anemia has not previously been reported in rats. We observed 2 cases of severe anemia in female Sprague-Dawley rats after RYGB surgery. These cases prompted us to further investigate the frequency and severity of anemia after RYGB in rats. Blood work and necropsies were performed on 9 additional female Sprague-Dawley rats (5 with RYGB, 4 with sham surgery). In these 9 rats, only one had signs of clinical anemia. These 3 anemic rats displayed moderate to severe pallor of the eyes and ears. Necropsy findings in anemic RYGB rats included pale internal organs and eccentric heart enlargement, which led to a significantly higher heart:body weight ratio in RYGB rats as compared with sham controls. Anemic rats had either a macrocytic normochromic anemia, consistent with vitamin B12 or folate deficiency, or microcytic hypochromic anemia, indicative of iron deficiency. Researchers who perform RYGB surgery in rats should be aware of the potential complication of severe anemia. Plans for the diagnosis and management of this complication and the development of criteria for humane endpoints for severe anemia are recommended as a refinement to these studies.

Roux-en-Y胃旁路手术(RYGB)是人类最常用的减肥手术之一。然而,这一过程并非没有风险,患者可能会出现并发症,包括小肠梗阻、胃肠道出血、慢性腹泻、溃疡、营养不良和贫血。特别是,贫血是一种公认的长期并发症,可能很严重。以大鼠为模型研究胃分流术的效果。它们可以经历与人类相似的并发症,但以前没有在老鼠身上报道过严重贫血的发展。我们观察到2例雌性Sprague-Dawley大鼠RYGB手术后严重贫血。这些病例促使我们进一步研究大鼠RYGB后贫血的频率和严重程度。另外对9只雌性Sprague-Dawley大鼠进行了血液检查和尸检(5只采用RYGB, 4只采用假手术)。在这9只大鼠中,只有一只有临床贫血的迹象。这3只贫血大鼠的眼睛和耳朵出现中度至重度苍白。贫血RYGB大鼠的尸检结果包括内脏苍白和心脏偏心增大,导致RYGB大鼠的心重比明显高于假对照组。贫血大鼠要么是大细胞正色性贫血,与维生素B12或叶酸缺乏一致,要么是小细胞低色性贫血,表明缺铁。在大鼠身上进行RYGB手术的研究人员应该意识到严重贫血的潜在并发症。建议制定诊断和管理该并发症的计划,并制定严重贫血的人道终点标准,作为这些研究的改进。
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引用次数: 0
Bacterial Genotype, Carrier Risk Factors, and an Antimicrobial Stewardship Approach Relevant To Methicillin-resistant Staphylococcus Aureus Prevalence in a Population of Macaques Housed in a Research Facility. 研究机构饲养的猕猴群体中与耐甲氧西林金黄色葡萄球菌流行率相关的细菌基因型、携带者风险因素和抗菌药物管理方法。
IF 1.3 4区 农林科学 Q2 VETERINARY SCIENCES Pub Date : 2023-04-01 Epub Date: 2023-03-20 DOI: 10.30802/AALAS-CM-22-000018
Matthew W Breed, Hannah L Perez, Michael Otto, Amer E Villaruz, J Scott Weese, Gregory W Alvord, Duncan E Donohue, Franchasca Washington, Joshua A Kramer

Methicillin-resistant Staphylococcus aureus (MRSA) remains a significant problem for human and animal health and can negatively affect the health status of macaques and other nonhuman primates (NHP) in research colonies. However, few publications provide guidance on the prevalence, genotype, or risk factors for macaques with MRSA and even fewer on how to effectively respond to MRSA once identified in a population. After having a clinical case of MRSA in a rhesus macaque, we sought to determine the MRSA carrier prevalence, risk factors, and genotypes of MRSA in a population of research NHPs. Over a 6-wk period in 2015, we collected nasal swabs from 298 NHPs. MRSA was isolated from 28% (n = 83). We then reviewed each macaque's medical record for a variety of variables including animal housing room, sex, age, number of antibiotic courses, number of surgical interventions, and SIV status. Analysis of these data suggests that MRSA carriage is associated with the room location, age of the animal, SIV status, and the number of antibiotic courses. We used multilocus sequence typing and spa typing on a subset of MRSA and MSSA isolates to determine whether the MRSA present in NHPs was comparable with common human strains. Two MRSA sequence types were predominant: ST188 and a novel MRSA genotype, neither of which is a common human isolate in the United States. We subsequently implemented antimicrobial stewardship practices (significantly reducing antimicrobial use) and then resampled the colony in 2018 and found that MRSA carriage had fallen to 9% (26/285). These data suggest that, as in humans, macaques may have a high carrier status of MRSA despite low clinically apparent disease. Implementing strategic antimicrobial stewardship practices resulted in a marked reduction in MRSA carriage in the NHP colony, highlighting the importance of limiting antimicrobial use when possible.

耐甲氧西林金黄色葡萄球菌(MRSA)仍然是人类和动物健康的一个重大问题,并可能对研究群体中猕猴和其他非人灵长类动物(NHP)的健康状况产生负面影响。然而,很少有出版物提供关于猕猴耐甲氧西林金黄色葡萄球菌的流行率、基因型或风险因素的指导,更少的出版物提供一旦在人群中发现如何有效应对耐甲氧氯化金黄色葡萄菌的指导。在恒河猴中出现耐甲氧西林金黄色葡萄球菌临床病例后,我们试图确定研究NHP人群中耐甲氧氯化金黄色葡萄菌携带者的患病率、危险因素和耐甲氧浓度基因型。在2015年的6周时间里,我们收集了298名NHP的鼻拭子。MRSA分离率为28%(n=83)。然后,我们审查了每只猕猴的医疗记录中的各种变量,包括动物饲养室、性别、年龄、抗生素疗程数、手术干预次数和SIV状态。对这些数据的分析表明,MRSA携带与房间位置、动物年龄、SIV状态和抗生素疗程数量有关。我们对MRSA和MSSA分离株的一个子集进行了多点序列分型和spa分型,以确定NHP中存在的MRSA是否与常见的人类菌株具有可比性。两种MRSA序列类型占主导地位:ST188和一种新的MRSA基因型,这两种基因型在美国都不是常见的人类分离株。随后,我们实施了抗菌药物管理实践(显著减少了抗菌药物的使用),然后在2018年对菌落进行了重新采样,发现MRSA携带率已降至9%(26/285)。这些数据表明,与人类一样,猕猴可能具有较高的耐甲氧西林金黄色葡萄球菌携带者状态,尽管其临床明显疾病较低。实施战略性抗菌药物管理实践显著减少了NHP菌落中MRSA的携带,突出了在可能的情况下限制抗菌药物使用的重要性。
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引用次数: 0
Bioactivity and Pharmacodynamics of X002, A Follicle-Stimulating Hormone-IgG4 Fc Fusion Protein. X002的生物活性和药效学,一个卵泡刺激激素IgG4-Fc融合蛋白。
IF 1.3 4区 农林科学 Q2 VETERINARY SCIENCES Pub Date : 2023-04-01 DOI: 10.30802/AALAS-CM-22-000001
Guili Xu, Yi Yang, Yunhui Liu, Fang Chen, Lihou Dong, Deyou Wan, Hongjie Li, Cuima Yang, Xin Gao

Current follicle-stimulating hormone (FSH) drugs meet safety criteria but have suboptimal efficacy, poor patient compliance, and high cost. Alternative FSH-like drugs would help to meet the high market demand. Here, we evaluated X002, an FSH-Fc fusion protein, for bioactivity and half-life in vitro and in vivo. In all cases, the effects of X002 were compared with those of a commercially available short-acting FSH recombinant hormone. First, female Kunming mice (age, 21 to 24 d) were stimulated with pregnant mare serum gonadotropin (PMSG) for 46 h, after which naked oocytes were harvested, treated with X002 or the comparison agent at 37 °C for 4 h, and then evaluated for germinal vesicle breakdown. Second, cumulus-oocyte complexes (COC) were collected from PMSG-stimulated mice and cocultured with X002 or the comparison agent for 14 h; the COC diameters were then measured, and the expression of genes involved in COC expansion were evaluated using quantitative RT-PCR analysis. Third, to assess the pharmacokinetics of X002, female Sprague-Dawley rats (age, 6 to 8 wk) were injected subcutaneously with X002 or the comparison agent; serum samples then were collected at various times and assessed via ELISA. Fourth, to evaluate X002 pharmacodynamics, 26-d-old female Sprague-Dawley rats were treated with X002 or the comparison agent; 84 h later, the rats were stimulated with human chorionic gonadotropin (hCG). At 12 h after hCG injection, euthanasia was performed. Ovaries were removed and weighed, and serum levels of estradiol and progesterone were measured. Finally, to assess superovulation, the oocytes in the fallopian tubes were counted at 108 h after in vivo treatment of rats with X002 or the comparison agent. The data show that X002, a long-acting agent, promoted germinal vesicle breakdown and COC expansion in vitro and in vivo ovarian weight gain and superovulation to a degree similar to the short-acting comparison agent.

目前的卵泡刺激素(FSH)药物符合安全标准,但疗效不佳,患者依从性差,成本高。替代类FSH药物将有助于满足高市场需求。在这里,我们评估了X002,一种FSH-Fc融合蛋白,在体外和体内的生物活性和半衰期。在所有情况下,将X002的效果与市售的短效FSH重组激素的效果进行比较。首先,用孕马血清促性腺激素(PMSG)刺激雌性昆明小鼠(年龄,21-24天)46小时,然后收获裸卵母细胞,用X002或对照剂在37°C下处理4小时,然后评估生发泡破裂。其次,从PMSG刺激的小鼠中收集卵丘-卵母细胞复合物(COC),并与X002或对照剂共培养14小时;然后测量COC直径,并使用定量RT-PCR分析评估参与COC扩增的基因的表达。第三,为了评估X002的药代动力学,雌性Sprague-Dawley大鼠(年龄,6-8周)皮下注射X002或对照剂;然后在不同时间收集血清样品并通过ELISA进行评估。第四,为了评价X002的药效学,用X002或对照剂治疗26日龄雌性Sprague-Dawley大鼠;84小时后,用人绒毛膜促性腺激素(hCG)刺激大鼠。在注射hCG后12小时,进行安乐死。取出卵巢并称重,测量血清雌二醇和孕酮水平。最后,为了评估超排卵,在用X002或对照剂对大鼠进行体内治疗后108小时,对输卵管中的卵母细胞进行计数。数据显示,X002是一种长效制剂,在体外和体内促进生发囊泡破裂和COC扩张,卵巢增重和超排卵的程度与短效对照剂相似。
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引用次数: 0
Effects of Mouse Kidney Parvovirus on Pharmacokinetics of Chemotherapeutics and the Adenine Model of Chronic Kidney Disease. 小鼠肾脏细小病毒对慢性肾脏病化疗药物动力学和腺嘌呤模型的影响。
IF 1.3 4区 农林科学 Q2 VETERINARY SCIENCES Pub Date : 2023-04-01 Epub Date: 2023-03-27 DOI: 10.30802/AALAS-CM-22-000084
Amanda C Ritter, Rodolfo Ricart J Arbona, Robert S Livingston, Sébastien Monette, Neil S Lipman

Mouse kidney parvovirus (MKPV) causes inclusion body nephropathy in severely immunocompromised mice and renal interstitial inflammation in immunocompetent mice. Here we sought to determine the effects of MKPV on pre-clinical murine models that depend on renal function. To assess the effects of MKPV infection on the pharmacokinetics of 2 renally excreted chemotherapeutic agents, methotrexate and lenalidomide, we measured drug concentrations in the blood and urine of MKPV-infected or uninfected immunodeficient NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) and immunocompetent C57BL/6NCrl (B6) female mice. No differences in plasma pharmacokinetics were observed for lenalidomide. However, the AUC of methotrexate was 1.5-fold higher in uninfected NSG mice compared with infected NSG mice, 1.9-fold higher in infected B6 mice compared with uninfected B6 mice, and 4.3-fold higher in uninfected NSG mice compared with uninfected B6 mice. MKPV infection did not significantly affect the renal clearance of either drug. To assess effects of MKPV infection on the adenine diet model of chronic kidney disease, MKPV-infected and uninfected B6 female mice were fed a 0.2% adenine diet, and clinical and histopathologic features of disease were assessed over 8 wk. MKPV infection did not significantly alter urine chemistry results, hemogram findings, or serum concentrations of BUN, creatinine, or symmetric dimethylarginine. However, infection did influence histologic outcomes. As compared with uninfected mice, MKPV-infected mice had more interstitial lymphoplasmacytic infiltrates after 4 and 8 wk of diet consumption and less interstitial fibrosis at week 8. Macrophage infiltrates and renal tubular injury were similar between in infected and uninfected mice. These findings indicate that MKPV infection had minimal effects on the renal excretion of 2 chemotherapeutics and on serum biomarkers of renal function. However, infection significantly influenced two histologic features of the adenine diet model of chronic renal disease. MKPV-free mice are critically important in studies evaluating renal histology as an experimental outcome.

小鼠肾细小病毒(MKPV)在免疫功能严重受损的小鼠中引起包涵体肾病,在免疫功能正常的小鼠中导致肾间质炎症。在这里,我们试图确定MKPV对依赖于肾功能的临床前小鼠模型的影响。为了评估MKPV感染对2种经肾排泄的化疗药物甲氨蝶呤和来那度胺的药代动力学的影响,我们测量了MKPV感染或未感染的免疫缺陷NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ(NSG)和免疫活性C57BL/6NCrl(B6)雌性小鼠血液和尿液中的药物浓度。来那度胺的血浆药代动力学没有观察到差异。然而,甲氨蝶呤的AUC在未感染的NSG小鼠中比感染的NSG小鼠高1.5倍,在感染的B6小鼠中比未感染的B6鼠高1.9倍,在未感染NSG小鼠的AUC比未感染B6鼠高4.3倍。MKPV感染对两种药物的肾清除率均无显著影响。为了评估MKPV感染对慢性肾脏疾病腺嘌呤饮食模型的影响,MKPV感染和未感染的B6雌性小鼠喂食0.2%腺嘌呤饮食,并在8周内评估疾病的临床和组织病理学特征。MKPV感染不会显著改变尿液化学结果、血象结果或BUN、肌酸酐或对称二甲基精氨酸的血清浓度。然而,感染确实会影响组织学结果。与未感染的小鼠相比,MKPV感染的小鼠在饮食摄入4周和8周后有更多的间质淋巴浆细胞浸润,在第8周时有更少的间质纤维化。感染和未感染小鼠的巨噬细胞浸润和肾小管损伤相似。这些发现表明,MKPV感染对2种化疗药物的肾脏排泄和肾功能的血清生物标志物的影响最小。然而,感染显著影响了慢性肾脏疾病腺嘌呤饮食模型的两个组织学特征。无MKPV的小鼠在评估肾脏组织学作为实验结果的研究中至关重要。
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引用次数: 0
Imaging and Pathologic Evaluation of Cryoablation of Woodchuck (Marmota Monax) Hepatocellular Carcinoma. 木拨鼠肝细胞癌冷冻消融的影像学和病理学评价。
IF 1.3 4区 农林科学 Q2 VETERINARY SCIENCES Pub Date : 2023-04-01 Epub Date: 2023-03-13 DOI: 10.30802/AALAS-CM-22-000092
Juan A Esparza-Trujillo, William F Pritchard, Michal Mauda-Havakuk, Matthew F Starost, Paul Wakim, Johnathan Zeng, Andrew S Mikhail, Ivane Bakhutashvili, Bradford J Wood, John W Karanian

We characterized cryoablation as a mode of clinical intervention in adult woodchucks with hepatocellular carcinoma (HCC). Woodchucks (n = 4) were infected with woodchuck hepatitis virus at birth and developed LI-RADS-5 hypervascular HCC. At 21 mo of age, they underwent ultrasound (US), contrast-enhanced CT (CECT) imaging, and US-guided subtotal cryoablation (IcePearl 2.1 CX, Galil, BTG) of their largest tumor (Mean HCC volume of 49 ± 9 cm³). Cryoablation was performed using two 10-min freeze cycles, each followed by an 8-min thaw cycle. The first woodchuck developed significant hemorrhage after the procedure and was euthanized. In the other 3 woodchucks, the probe track was cauterized and all 3 completed the study. Fourteen days after ablation, CECT was performed, and woodchucks were euthanized. Explanted tumors were sectioned using subject-specific, 3D-printed cutting molds. Initial tumor volume, the size of the cryoablation ice ball, gross pathology and hematoxylin and eosin-stained tissue sections were evaluated. On US, the edges of the solid ice balls were echogenic with dense acoustic shadowing and average dimensions of 3.1 ± 0.5 × 2.1 ± 0.4 cm and cross-sectional area of 4.7 ± 1.0 cm ². On day 14 after cryoablation, CECT of the 3 woodchucks showed devascularized hypo-attenuating cryolesions with dimensions of 2.8 ± 0.3 × 2.6 ± 0.4 × 2.93 ± 0.7 cm and a cross-sectional area of 5.8 ± 1.2 cm². Histopathologic evaluation showed hemorrhagic necrosis with a central amorphous region of coagulative necrosis surrounded by a rim of karyorrhectic debris. A rim of approximately 2.5 mm of coagulative necrosis and fibrous connective tissue clearly demarcated the cryolesion from adjacent HCC. Partial cryoablation of tumors produced coagulative necrosis with well-defined ablation margins at 14 d. Cauterization appeared to prevent hemorrhage after cryoablation of hypervascular tumors. Our findings indicate that woodchucks with HCC may provide a predictive preclinical model for investigating ablative modalities and developing new combination therapies.

我们将冷冻消融作为一种临床干预方式,用于治疗患有肝细胞癌(HCC)的成年土拨鼠。土拨鼠(n=4)在出生时感染了土拨鼠肝炎病毒,并发展为LI-RADS-5高血管HCC。在21个月大时,他们接受了超声(US)、对比增强CT(CECT)成像和US引导的大部冷冻消融(IcePearl 2.1 CX,Galil,BTG),切除了他们最大的肿瘤(平均HCC体积为49±9 cm³)。冷冻消融使用两个10分钟的冷冻循环进行,每个循环之后是8分钟的解冻循环。第一只土拨鼠在手术后出现严重出血,并被安乐死。在另外3只土拨鼠中,探针轨迹被烧灼,3只都完成了研究。消融术后14天,进行CECT,并对土拨鼠实施安乐死。使用受试者专用的3D打印切割模具对移植的肿瘤进行切片。评估初始肿瘤体积、冷冻消融冰球的大小、大体病理学以及苏木精和伊红染色的组织切片。在US上,固体冰球的边缘具有回声,有密集的声学阴影,平均尺寸为3.1±0.5×2.1±0.4 cm,横截面积为4.7±1.0 cm²。冷冻消融后第14天,3只土拨鼠的CECT显示断流低衰减冷冻损伤,尺寸为2.8±0.3×2.6±0.4×2.93±0.7cm,横截面积为5.8±1.2cm²。组织病理学评估显示出血性坏死,中心无定形凝固性坏死区域被核碎裂碎片包围。大约2.5毫米的凝固性坏死和纤维结缔组织的边缘清楚地将冷冻损伤与邻近的HCC区分开来。肿瘤的部分冷冻消融在14d时产生凝固性坏死,消融边缘清晰。在冷冻消融高血管肿瘤后,烧灼似乎可以防止出血。我们的研究结果表明,患有HCC的土拨鼠可能为研究消融模式和开发新的联合疗法提供一个预测性的临床前模型。
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引用次数: 0
Comparison of a Minimally Invasive Transthoracic Approach and a Surgical Method For Intrapleural Injection of Tumor Cells in Mice. 微创经胸入路和手术方法在小鼠胸膜内注射肿瘤细胞的比较。
IF 1.3 4区 农林科学 Q2 VETERINARY SCIENCES Pub Date : 2023-04-01 Epub Date: 2023-03-15 DOI: 10.30802/AALAS-CM-22-000044
Jiajie Jessica Xu, Melissa Y Lucero, Nicole L Herndon, Michael C Lee, Jefferson Chan

Intrapleural injections can be used in mice to deliver therapeutic and diagnostic agents and to model human disease processes (for example, pleural fluid accumulation, malignant pleural disease, and lung cancers). In the context of establishing cancer models, minimally invasive methods of intrapleural injection are desirable because inflammation at the injection site can have a major impact on tumor growth and progression. Common approaches for intrapleural injection include surgical exposure of the thoracic wall or the diaphragm prior to injection; however, these invasive procedures require tissue dissection that triggers an undesirable inflammatory response and increases the risk of pneumothorax. While nonsurgical procedures can minimize this concern, 'blind' injections may lead to off-target inoculation. In this study, we hypothesized that a minimally invasive transthoracic approach (MI-TT) would produce a tumor distribution and burden similar to that of a surgical transabdominal approach (SX-TA). Prior to performing the procedures on live mice, surgeons were trained using cadavers and terminal procedures. Then a total of 14 nude mice (female, 4 to 6 wk old) were injected with 50 μL (5 million) A549-Luc2 human cancer cells either using the MI-TT (n = 8) or SX-TA (n = 6) approach under carprofen analgesia and isoflurane anesthesia. Our results indicate that with training, a minimally invasive transthoracic approach for intrapleural injection provides more consistent tumor placement and a greater tumor burden than does the surgical method. However, additional studies are necessary to confirm anatomic placement and characterize tumor profiles.

胸膜内注射可用于小鼠递送治疗剂和诊断剂,并模拟人类疾病过程(例如,胸腔积液、恶性胸膜疾病和肺癌)。在建立癌症模型的背景下,胸膜内注射的微创方法是可取的,因为注射部位的炎症可能对肿瘤生长和进展产生重大影响。胸膜内注射的常见方法包括在注射前手术暴露胸壁或膈肌;然而,这些侵入性手术需要进行组织解剖,这会引发不理想的炎症反应,并增加患肺气肿的风险。虽然非手术程序可以最大限度地减少这种担忧,但“盲目”注射可能会导致脱靶接种。在这项研究中,我们假设微创经胸入路(MI-TT)会产生与外科经腹部入路(SX-TA)相似的肿瘤分布和负担。在对活体小鼠进行手术之前,外科医生接受了尸体和末端手术的训练。然后用MI-TT(n=8)或SX-TA(n=6)方法,在卡洛芬镇痛和异氟烷麻醉下,向总共14只裸鼠(雌性,4至6周大)注射50μL(500万)A549-Luc2人癌症细胞。我们的研究结果表明,通过训练,胸膜内注射的微创经胸入路比手术方法提供了更一致的肿瘤放置和更大的肿瘤负担。然而,需要进行更多的研究来确认解剖位置和肿瘤特征。
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引用次数: 0
Bacterial Cholecystitis and Cholangiohepatitis in Common Marmosets (Callithrix Jacchus). 普通马齿苋的细菌性胆囊炎和胆管性肝炎。
IF 1.3 4区 农林科学 Q2 VETERINARY SCIENCES Pub Date : 2023-04-01 Epub Date: 2023-03-21 DOI: 10.30802/AALAS-CM-22-000075
Sarah J Powers, Natalie Castell, Rachel Vistein, Anthony N Kalloo, Jessica M Izzi, Kathleen L Gabrielson

The common marmoset (Callithrix jacchus), a New World NHP, has emerged as important animal model in multiple areas of translational biomedical research. The quality of translational research in marmosets depends on early diagnosis, treatment, and prevention of their spontaneous diseases. Here, we characterize an outbreak of infectious cholangiohepatitis that affected 7 adult common marmosets in a single building over a 10-mo period. Marmosets presented for acute onset of lethargy, dull mentation, weight loss, dehydration, hyporexia, and hypothermia. Blood chemistries at presentation revealed markedly elevated hepatic and biliary enzymes, but mild neutrophilia was detected in only 1 of the 7. Affected marmosets were unresponsive to rigorous treatment and died or were euthanized within 48 h of presentation. Gross and histopathologic examinations revealed severe, necrosuppurative cholangiohepatitis and proliferative cholecystitis with bacterial colonies and an absence of gallstones. Perimortem and postmortem cultures revealed single or dual isolates of Escherichia coli and Pseudomonas aeruginosa. Other postmortem findings included bile duct hyperplasia, periportal hepatitis, bile peritonitis, ulcerative gastroenteritis, and typhlitis. Environmental contamination of water supply equipment with Pseudomonas spp. was identified as the source of infection, but pathogenesis remains unclear. This type of severe, infectious cholangiohepatitis with proliferative cholecystitis with Pseudomonas spp. had not been reported previously in marmosets, and we identified and here describe several contributing factors in addition to contaminated drinking water.

普通狨猴(Callithrix jacchus)是新世界的一种NHP,已成为转化生物医学研究的多个领域中的重要动物模型。狨转化研究的质量取决于其自发疾病的早期诊断、治疗和预防。在这里,我们描述了感染性胆管肝炎的爆发,在10个月的时间里,在一栋建筑里感染了7只成年普通狨。Marmosets表现为急性嗜睡、精神迟钝、体重减轻、脱水、低热和体温过低。呈现时的血液化学检查显示肝脏和胆汁酶显著升高,但7例中只有1例检测到轻度中性粒细胞增多症。受影响的狨猴对严格的治疗没有反应,在出现后48小时内死亡或被安乐死。大体和组织病理学检查显示严重的坏死性化脓性胆管肝炎和增生性胆囊炎,有菌落,无胆结石。尸检和死后培养显示大肠杆菌和铜绿假单胞菌的单一或双重分离株。其他尸检结果包括胆管增生、门周肝炎、胆汁性腹膜炎、溃疡性肠胃炎和斑疹伤寒。供水设备的环境被假单胞菌污染。已确定为感染源,但发病机制尚不清楚。这种类型的严重感染性胆管肝炎伴增生性胆囊炎伴假单胞菌属。以前从未在狨猴中报道过,我们确定并在此描述了除受污染的饮用水外的几个促成因素。
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引用次数: 0
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