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Animal Models

Brown, C. (2006). Blood collection from the cranial vena cava of the ferret. Lab Animal 35(9): 23-24. ISSN: 0093-7355.
NAL Call Number: QL55.A1L33
Abstract: The domestic ferret, though not as common a laboratory animal as the rat or mouse, serves as a model in critical research areas, including influenza biology and vaccine development. Studies involving ferrets necessitate knowledge of proper blood collection methods, such as cranial vena cava puncture.
Descriptors: ferret, blood collection, cranial vena cava, animal model, research.

Endo, T., M. Minami, M. Hirafuji, N. Hamaue, and S.H. Parvez (2004). The ferret: A cytotoxic drug-induced emesis model. Biogenic Amines 18(3-6): 419-434. ISSN: 0168-8561.
Descriptors: ferret, animal model, emesis, Mustela, cytotoxic drugs, vagus nerve, emetic stimuli, Cisplatin induced, vagotomy.

Gierdalski, M., S.P. Sardi, G. Corfas, and S.L. Juliano (2005). Endogenous neuregulin restores radial glia in a (ferret) model of cortical dysplasia. Journal of Neuroscience 25(37): 8498-8504. ISSN: 1529-2401.
Abstract: Radial glia are integral components of the developing neocortex. During corticogenesis, they form an important scaffold for neurons migrating into the cortical plate. Recent attention has focused on neuregulin (NRG1), acting through erbB receptors, in maintaining their morphology. We developed a model of developmental radial glial disruption by delivering an antimitotic [methylazoxy methanol (MAM)] to pregnant ferrets on embryonic day 24 (E24). We previously found that normal ferret cortex contains a soluble factor capable of realigning the disorganized radial glia back toward their normal morphology. Characterization of the reorganizing activity in normal cortex demonstrated that the probable factor mediating these responses was a 30-50 kDa protein. To test whether this endogenous soluble factor was NRG1, we used organotypic cultures of E24 MAM-treated ferret neocortex supplemented with the endogenous factor obtained from normal cortical implants, exogenous NRG1beta, antibodies that either blocked or stimulated erbB receptors, or a soluble erbB subtype that binds to available NRG1. We report that exogenous NRG1 or antibodies that stimulate erbB receptors dramatically improve the morphology of disrupted radial glia, whereas blockade of NRG1-erbB signaling prevents the radial glial repair. Our results suggest that NRG1 is an endogenous factor in ferret neocortex capable of repairing damaged radial glia and that it acts via one or more erbB receptors.
Descriptors: ferrets, cerebral cortex, neuregulins, neuroglia, animal models, newborn disease models, methylazoxymethanol acetate, prenatal exposure, corticogenesis.

He, T., H. Friede, and S. Kiliaridis (2002). Dental eruption and exfoliation chronology in the ferret (Mustela putorius furo). Archives of Oral Biology 47(8): 619-623. ISSN: 0003-9969.
NAL Call Number: RK1.A6989
Abstract: Substituting ferrets for rats and dogs as animal models for craniofacial research is favourable because of the similarity of many of the ferret's anatomical, metabolic and physiological features to those of man. Other advantages are cost-effectiveness and possibly less ethical controversy. However, information on the dental chronology of ferrets needs to be supplemented if this animal is to be promoted as an alternative model. Dental development was here examined in 16 ferrets (eight males, eight females) from three litters at between 12 and 90 days of age. Dental eruption and exfoliation were assessed and recorded every second day. The sequence of eruption of deciduous and permanent teeth was determined and data were analysed statistically. Also, any sex-related differences in eruption and exfoliation ages were defined. No deciduous incisors were observed to erupt in this group of animals. Other deciduous teeth erupted between the 19th and 31st postnatal days, and exfoliated between days 51 and 76. The time of eruption of the permanent teeth ranged from 42 to 77 days, in accordance with the stage of the mixed dentition. The female ferrets were generally ahead of the males in the exfoliation age of their deciduous teeth and the eruption age of their permanent teeth, but this, a sex difference did not apply to the eruption age of the deciduous teeth. These extended basic data might facilitate the introduction of this alternative experimental animal into craniofacial research.
Descriptors: ferrets physiology, animal models, tooth eruption physiology, tooth exfoliation, deciduous teeth, aging physiology, sex factors.

He, T. and S. Kiliaridis (2003). Effects of masticatory muscle function on craniofacial morphology in growing ferrets (Mustela putorius furo). European Journal of Oral Sciences 111(6): 510-517. ISSN: 0909-8836.
Abstract: Studying the effects of masticatory muscle function on craniofacial morphology in animal models with different masticatory systems is important for further understanding of related issues in humans. Forty 5-wk-old male ferrets were equally divided into two groups. One group was fed a diet of hard pellets (HDG) and the other group was fed the same diet but softened with water (SDG). Lateral and dorsoventral cephalograms were taken on each group after 6 months. Cephalometric measurements were performed by digital procedures. For SDG ferrets, the hard palate plane was more distant from the cranial base plane, and canines were more proclined compared with HDG ferrets. The SDG ferrets were also found to have smaller interfrontal and interparietal widths, and a slenderer zygomatic arch than the HDG ferrets. In the mandible, the coronoid process was generally shorter and narrower for the SDG ferrets. The effects of the altered masticatory muscle function on craniofacial morphology in growing ferrets seemed to differ from those previously reported in other animal models studied under similar experimental conditions. Such differences in the effects are presumably related to the differences in the mode of mastication, craniofacial anatomy and growth pattern in different animal models.
Descriptors: ferret growth and development, mastication, masticatory muscles, maxillofacial development, skull growth and development, feed, nutrition, facial bones, mandible.

Herlocher, M.L., R. Truscon, R. Fenton, A. Klimov, S. Elias, S.E. Ohmit, and A.S. Monto (2003). Assessment of development of resistance to antivirals in the ferret model of influenza virus infection. Journal of Infectious Diseases 188(9): 1355-1361. ISSN: 0022-1899.
NAL Call Number: 448.8 J821
Abstract: We attempted to develop in vivo resistance of influenza virus to amantadine and to zanamivir, by use of the ferret model of influenza virus infection. Resistance of influenza virus A/LosAngeles/1/87 (H3N2) to amantadine was generated within 6 days, during a single course of treatment, and mutations in the M2 gene that are characteristic of human infections were observed. In contrast, during an identical single course of treatment with zanamivir, no evidence of reduced susceptibility was demonstrated. Pooled virus shed by zanamivir-treated ferrets was used to infect another group of ferrets. Twenty virus clones grew in plaque assays containing zanamivir, indicating possible reduced susceptibility; however, none exhibited reduced susceptibility to zanamivir in neuraminidase (NA) inhibition assays. Sequencing of the NA gene of these clones revealed only a noncoding nucleotide mutation at position 685. Sequencing of the hemagglutinin gene revealed mutations at positions 53, 106, 138, 145, 166, and 186. Similar to the situation in humans, amantadine use in ferrets rapidly produces antiviral resistance, but zanamivir use does not, although nucleotide changes were observed.
Descriptors: ferrets, amantadine, antiviral agents, influenza A virus, orthomyxoviridae infections, sialic acids, animal disease models, drug resistance, viral genetics, guanidines, hemagglutination inhibition tests, viral chemistry, RNA, reverse transcriptase polymerase chain reaction, DNA sequence analysis.

Howard, J., P.E. Marinari, and D.E. Wildt (2003). Black-footed ferret: Model for assisted reproductive technologies contributing to in situ conservation. Conservation Biology Series 8: 249-266.
Descriptors: Mustela nigripes, black footed ferrets, breeding and reintroduction program, USA, reproductive technology, in situ conservation.

Jacobs, K.M. (2004). A ferret model of microgyria: The effect of varying lesion days. Epilepsia 45(Suppl. 7): 44. ISSN: 0013-9580.
Descriptors: ferrets as animal models, microgyria, varying lesions, nervous system diseases, epilepsy.
Notes: 58th Annual Meeting of the American-Epilepsy-Society, New Orleans, LA, USA; December 03 -07, 2004.

Johnson Delaney, C.A. (2005). The ferret gastrointestinal tract and Helicobacter mustelae infection. Veterinary Clinics of North America. Exotic Animal Practice 8(2): 197-212. ISSN: 1094-9194.
NAL Call Number: SF997.5.E95 E97
Descriptors: ferrets, microbiology, gastrointestinal tract, helicobacter infections, Helicobacter mustelae pathogenicity, biliary tract, disease models, pancreas, exocrine physiology.

Kim, Y., N. Chongviriyaphan, C. Liu, R.M. Russell, and X.D. Wang (2006). Combined antioxidant (beta-carotene, alpha-tocopherol and ascorbic acid) supplementation increases the levels of lung retinoic acid and inhibits the activation of mitogen-activated protein kinase in the ferret lung cancer model. Carcinogenesis 27(7): 1410-1419. ISSN: 0143-3334.
Abstract: Interactions among beta-carotene (BC), alpha-tocopherol (AT) and ascorbic acid (AA) led to the hypothesis that using a combination of these antioxidants could be more beneficial than using a single antioxidant alone, particularly against smoke-related lung cancer. In this investigation, we have conducted an animal study to determine whether combined BC, AT and AA supplementation (AOX) protects against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung carcinogenesis in smoke-exposed (SM) ferrets. Ferrets were treated for 6 months in the following four groups: (i) control, (ii) SM + NNK, (iii) AOX and (iv) SM + NNK + AOX. Results showed that the combined AOX supplementation (i) prevented the SM + NNK-decreased lung concentrations of retinoic acid (RA) and BC; (ii) inhibited the SM + NNK-induced phosphorylation of Jun N-terminal kinase (JNK), extracellular-signal-regulated protein kinase (ERK) and proliferating cellular nuclear antigen proteins in the lungs of ferrets; and (iii) blocked the SM + NNK-induced up-regulation of total p53 and Bax proteins, as well as phosphorylated p53 in the lungs of ferrets. In addition, there were no lesions observed in the lung tissue of ferrets in the control and/or the AOX groups after 6 months of intervention, but combined AOX supplementation resulted in a trend toward lower incidence of both preneoplastic lung lesions and lung tumor formation in SM + NNK + AOX group of ferrets, as compared with the SM + NNK group alone. These data indicate that combined AOX supplementation could be a useful chemopreventive strategy against lung carcinogenesis through maintaining normal tissue levels of RA and inhibiting the activation of mitogen-activated protein kinase pathways, cell proliferation and phosphorylation of p53.
Descriptors: ferrets, animal model, lung neoplasms, ascorbic acid, carcinogens, immunohistochemistry, lung metabolism, nitrosamines, tobacco smoke pollution, tumor suppressor, protein metabolism, beta carotene.

Kim, Y., X. Liu S, C. Liu, D. Smith E, R. Russell M, and X. Wang D (2006). Induction of pulmonary neoplasia in the smoke-exposed ferret by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK): A model for human lung cancer. Cancer Letters 234(2): 209-219. ISSN: 0304-3835.
Abstract: Research into dietary chemoprevention against lung carcinogenesis has been limited by the lack of appropriate animal models that closely mimic smoking-related human lung cancer. Ferrets (Mustela putorius furo) have been used to study the biologic activities of carotenoids against smoke-induced lung lesions, but this model has yet to be thoroughly established and validated. To determine the appropriateness of the ferret as a model for human lung cancer, we have performed a 6-month in vivo study in ferrets exposed to both tobacco smoke and a carcinogen (4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone, NNK) found in cigarette smoke. Results showed that six out 12 ferrets exposed to both NNK injection and cigarette smoke developed grossly identifiable lung tumors whereas none of nine ferrets from the sham treatment group developed any lung lesions. The histopathological types of these tumors (squamous cell carcinoma, adenosquamous carcinoma and adenocarcinoma) in ferret lungs are very similar to those in humans. In addition, 10 out of 12 ferrets exposed to both NNK and cigarette smoke developed preneoplastic lesions (squamous metaplasia, dysplasia, and atypical adenomatous hyperplasia) with complex growth patterns whereas the sham group did not show any of these lesions. Furthermore, the expression of proliferating cellular nuclear antigen increased markedly in both gross tumors and preneoplastic lesions in the lungs. In summary, the development of both preneoplastic lesions and gross lung tumors in ferrets provides an excellent and unique model for studying lung cancer chemoprevention with agents such as carotenoids, and for studying the molecular mechanism of carcinogenesis in the earlier stages of smoke-related lung cancer.
Descriptors: ferret, animal model, lung carcinogenesis, lung cancer, pulmonary neoplasia, carotenoids, cigarette smoke.

Lambkin, R., J.S. Oxford, S. Bossuyt, A. Mann, I.C. Metcalfe, C. Herzog, J.F. Viret, and R. Gluck (2004). Strong local and systemic protective immunity induced in the ferret model by an intranasal virosome-formulated influenza subunit vaccine. Vaccine 22(31-32): 4390-4396. ISSN: 0264-410X.
NAL Call Number: QR189.V32
Abstract: The proliferation of influenza viruses causes costly, recurrent, annual epidemics. Current vaccines, mainly administered parenterally, have been shown to be suboptimal in terms of efficacy, particularly where local IgA responses are concerned. Recent investigations of virosomes as delivery systems for viral HA and NA antigens have demonstrated an improved immune response. This paper investigates the efficacy of a novel virosome-based intranasal influenza vaccine by its ability to reduce disease symptoms and its effect on viral shedding in nasal secretions of immunised ferrets. The use of ferrets in the study of influenza vaccines is based on the good comparability between ferret and human response to the disease. Intranasal, as opposed to parenteral, administration of a trivalent virosome-based subunit vaccine adjuvanted with HLT provides an almost total prevention of virus shedding combined with a high level of immunological protection against homologous virus challenge. The ease of application of an intranasal vaccine may have positive repercussions in the adoption of influenza vaccinations, particularly in 'at-risk' groups.
Descriptors: ferrets, orthomyxoviridae infections, intranasal administration, influenza A virus, influenza B virus, influenza vaccines, orthomyxoviridae infections, virus shedding.

Lau, A.H.Y., K.K.W. Kan, H.W. Lai, M.P. Ngan, J.A. Rudd, and D.T.W. Yew (2003). Action of emetic drugs in the ferret and Suncus murinus (house musk shrew): New models of nausea? Journal of Veterinary Pharmacology and Therapeutics 26(Supplement 1): 157. ISSN: 0140-7783.
NAL Call Number: SF915.J63
Descriptors: emesis, ferret, musk shrew, animal models, emetic drugs, action, nausea, meeting abstract.
Notes: Proceedings of the 9th International Congress of the European Association for Veterinary Pharmacology and Toxicology, Lisbon, Portugal; July 13-18, 2003.

Li, Z. and J.F. Engelhardt (2003). Progress toward generating a ferret model of cystic fibrosis by somatic cell nuclear transfer. Reproductive Biology and Endocrinology 1: 83. ISSN: 1477-7827.
Abstract: Mammalian cloning by nuclear transfer from somatic cells has created new opportunities to generate animal models of genetic diseases in species other than mice. Although genetic mouse models play a critical role in basic and applied research for numerous diseases, often mouse models do not adequately reproduce the human disease phenotype. Cystic fibrosis (CF) is one such disease. Targeted ablation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in mice does not adequately replicate spontaneous bacterial infections observed in the human CF lung. Hence, several laboratories are pursuing alternative animal models of CF in larger species such as the pig, sheep, rabbits, and ferrets. Our laboratory has focused on developing the ferret as a CF animal model. Over the past few years, we have investigated several experimental parameters required for gene targeting and nuclear transfer (NT) cloning in the ferret using somatic cells. In this review, we will discuss our progress and the hurdles to NT cloning and gene-targeting that accompany efforts to generate animal models of genetic diseases in species such as the ferret.
Descriptors: ferrets, cell nucleus transplantation, cystic fibrosis, animal disease models, cell nucleus, cloning, fibroblasts.

Li, Z., Q. Jiang, M. Rezaei Sabet, Y. Zhang, T.C. Ritchie, and J.F. Engelhardt (2002). Conditions for in vitro maturation and artificial activation of ferret oocytes. Biology of Reproduction 66(5): 1380-1386. ISSN: 0006-3363.
Abstract: The ferret represents an attractive species for animal modeling of lung diseases because of the similarity between ferret and human lung biology and its relatively small size and short gestation time. In an effort to establish experimental protocols necessary for cloning ferrets, optimized conditions for in vitro maturation and artificial activation of ferret oocytes were examined. Cumulus-oocyte complexes were harvested from ovaries of superovulated ferrets, and in vitro maturation was evaluated in three different culture media: medium 1 (TCM-199 + 10% FBS), medium 2 (TCM-199 + 10% FBS with eCG [10 IU/ml] and hCG [5 IU/ml]), or medium 3 (TCM-199 + 10% FBS with eCG, hCG, and 17beta-estradiol [2 microg/ml]). After 24 h of maturation in vitro, the maturation rate of oocytes cultured in medium 2 (70%, n = 79) was significantly greater (P < 0.01) than those of oocytes cultured in the other two media (27%-36%, n = 67-73). At 48 h, similar maturation rates (56%-69%, n = 76-87) were observed for all three types of media. For activation experiments, oocytes cultured in medium 2 were stimulated with electrical and chemical stimuli either individually or in combination. Treatment with cycloheximide and 6-dimethylaminopurine (6-DMAP) following electrical stimulation resulted in 43% (n = 58) of the oocytes developing to the blastocyst stage. Such an activation rate represented a significant improvement over those obtainable under other tested conditions, including individual treatment with electrical pulses (10%, n = 41), cycloheximide (3%, n = 58), or 6-DMAP (5%, n = 59). Blastocysts derived from in vitro activation appeared to be normal morphologically and were composed of an appropriate number of both inner cell mass (mean +/- SEM, 10.3 +/- 1.1; n = 11) and trophectoderm (60.8 +/- 2.9, n = 11) cells. These results have begun to elucidate parameters important for animal modeling and cloning with ferrets.
Descriptors: ferrets, oocytes, animal model, lung diseases, cycloheximide, electric stimulation, embryonic and fetal development, fertilization in vitro, parthenogenesis, protein synthesis inhibitors, superovulation, ferret lung, human lung, cloning.

Li, Z., X. Sun, J. Chen, G.H. Leno, and J.F. Engelhardt (2006). Factors affecting the efficiency of embryo transfer in the domestic ferret (Mustela putorius furo). Theriogenology 66(2): 183-190. ISSN: 0093-691X.
NAL Call Number: QP251.A1T5
Abstract: Embryo transfer (ET) to recipient females is a foundational strategy for a number of assisted reproductive technologies, including cloning by somatic cell nuclear transfer. In an attempt to develop efficient ET in domestic ferrets, factors affecting development of transferred embryo were investigated. Unilateral and bilateral transfer of zygotes or blastocysts in the oviduct or uterus was evaluated in recipient nulliparous or primiparous females. Developing fetuses were collected from recipient animals 21 days post-copulation and examined. The percentage of fetal formation was different (P < 0.05) for unilateral and bilateral transfer of zygotes (71%) in nulliparous females with bilateral transfer (56%) in primiparous recipients. The percentage (90%) of fetal formation in nulliparous recipients following unilateral transfer of blastocysts was higher (P < 0.05) than that observed in primiparous recipients with bilateral ET (73%). Notably, the percentage of fetal formation was higher (P < 0.05) when blastocyts were transferred as compared to zygotes (90% versus 71%). Transuterine migration of embryos occurred following all unilateral transfers and also in approximately 50% of bilateral transfers with different number of embryos in each uterine horn. These data will help to facilitate the development of assisted reproductive strategies in the ferret and could lead to the use of this species for modeling human disease and for conservation of the endangered Mustelidae species such as black-footed ferret and European mink.
Descriptors: ferret, embryo transfer, factors, efficiency, reproductive technologies, animal model.

Li, Z., X. Sun, J. Chen, X. Liu, S.M. Wisely, Q. Zhou, J.P. Renard, G.H. Leno, and J.F. Engelhardt (2006). Cloned ferrets produced by somatic cell nuclear transfer. Developmental Biology 293(2): 439-448. ISSN: 0012-1606.
NAL Call Number: 442.8 D49
Abstract: Somatic cell nuclear transfer (SCNT) offers great potential for developing better animal models of human disease. The domestic ferret (Mustela putorius furo) is an ideal animal model for influenza infections and potentially other human respiratory diseases such as cystic fibrosis, where mouse models have failed to reproduce the human disease phenotype. Here, we report the successful production of live cloned, reproductively competent, ferrets using species-specific SCNT methodologies. Critical to developing a successful SCNT protocol for the ferret was the finding that hormonal treatment, normally used for superovulation, adversely affected the developmental potential of recipient oocytes. The onset of Oct4 expression was delayed and incomplete in parthenogenetically activated oocytes collected from hormone-treated females relative to oocytes collected from females naturally mated with vasectomized males. Stimulation induced by mating and in vitro oocyte maturation produced the optimal oocyte recipient for SCNT. Although nuclear injection and cell fusion produced mid-term fetuses at equivalent rates (approximately 3-4%), only cell fusion gave rise to healthy surviving clones. Single cell fusion rates and the efficiency of SCNT were also enhanced by placing two somatic cells into the perivitelline space. These species-specific modifications facilitated the birth of live, healthy, and fertile cloned ferrets. The development of microsatellite genotyping for domestic ferrets confirmed that ferret clones were genetically derived from their respective somatic cells and unrelated to their surrogate mother. With this technology, it is now feasible to begin generating genetically defined ferrets for studying transmissible and inherited human lung diseases. Cloning of the domestic ferret may also aid in recovery and conservation of the endangered black-footed ferret and European mink.
Descriptors: ferrets, cell nucleus transplantation, cloning, genetics, cell fusion, embryo transfer, fetal development, microinjections, oocytes.

Liu, C., F. Lian, D.E. Smith, R.M. Russell, and X.D. Wang (2003). Lycopene supplementation inhibits lung squamous metaplasia and induces apoptosis via up-regulating insulin-like growth factor-binding protein 3 in cigarette smoke-exposed ferrets. Cancer Research 63(12): 3138-3144. ISSN: 0008-5472.
Abstract: Higher intake of lycopene is related to a lower risk of lung cancer in human studies. Lung cancer risk is associated with higher plasma levels of insulin-like growth factor I (IGF-I) and/or lower levels of IGF-binding protein 3 (IGFBP-3). However, little is known regarding whether lycopene can inhibit cigarette smoke-induced lung carcinogenesis through modulation of IGF-I/IGFBP-3, cell proliferation, and apoptosis. We investigated the effects of lycopene supplementation at a low dose (1.1 mg/kg/day, which is equivalent to an intake of 15 mg/day in humans) and a high dose (4.3 mg/kg/day, which is equivalent to 60 mg/day in humans) on plasma IGF-I/IGFBP-3 levels, histopathological changes, proliferating cellular nuclear antigen (PCNA) expression, BAD phosphorylation, and apoptosis (caspase 3 assay) in lungs of ferrets with or without cigarette smoke exposure for 9 weeks. We found that ferrets supplemented with lycopene and exposed to smoke had significantly higher plasma IGFBP-3 levels (P < 0.01) and a lower IGF-I/IGFBP-3 ratio (P < 0.01) than ferrets exposed to smoke alone. Both low- and high-dose lycopene supplementations substantially inhibited smoke-induced squamous metaplasia and PCNA expression in the lungs of ferrets. No squamous metaplasia or PCNA overexpression were found in the lungs of control ferrets or those supplemented with lycopene alone. Furthermore, cigarette smoke exposure greatly increased BAD phosphorylation at both Ser(136) and Ser(112) and significantly decreased cleaved caspase 3 in the lungs of ferrets, as compared with controls. The elevated phosphorylation of BAD and down-regulated apoptosis induced by cigarette smoke in the lungs of ferrets was prevented by both low- and high-dose lycopene supplementations. Lycopene levels were increased in a dose-dependent manner in both plasma and lungs of ferrets supplemented with lycopene alone. However, lycopene levels were markedly lower in both plasma and lungs of ferrets supplemented with lycopene and exposed to smoke. Furthermore, smoke exposure increased cis isomers (26% for 13-cis and 22% for 9-cis) of lycopene in the lungs of ferrets, compared with that of ferrets supplemented with lycopene alone (20% for 13-cis and 14% for 9-cis). In conclusion, lycopene may mediate its protective effects against smoke-induced lung carcinogenesis in ferrets through up-regulating IGFBP-3 and down-regulating phosphorylation of BAD, which promote apoptosis and inhibit cell proliferation.
Descriptors: ferrets, anticarcinogenic agents, apoptosis, carotenoids, adverse effects of smoke, anticarcinogenic agents, carrier proteins, caspases, cell division, dietary supplements, drug evaluation, lung metabolism, metaplasia, animal models, phosphorylation, post translational drug effects.

Liu, C., R.M. Russell, and X.D. Wang (2006). Lycopene supplementation prevents smoke-Iinduced changes in p53, p53 phosphorylation, cell proliferation, and apoptosis in the gastric mucosa of ferrets. Journal of Nutrition 136(1): 106-111. ISSN: 0022-3166.
NAL Call Number: 389.8 J82
Abstract: Cigarette smoking increases the risk for gastric cancer. Higher intakes or blood levels of lycopene are associated with a decreased risk of gastric cancer. However, the biological mechanisms by which lycopene may protect against gastric carcinogenesis are poorly understood. We evaluated the effects of lycopene supplementation on smoke-induced changes in protein levels of p53, p53 target genes (p21[superscript Waf1/Cip1] and Bax-1), cell proliferation, and apoptosis in the gastric mucosa of ferrets. Ferrets were assigned to cigarette smoke exposure or to no exposure and to no, low-dose, or high-dose lycopene supplementation (2 x 3 factorial design) for 9 wk. Lycopene concentrations were significantly elevated in a dose-dependent manner in the gastric mucosa of ferrets supplemented with lycopene alone, but were markedly reduced in ferrets supplemented with lycopene and exposed to smoke. Although ferrets were given lycopene containing 95% all-trans isomers, cis isomers were the predominant forms in the gastric mucosa. Total p53 and phosphorylated p53 levels were greater in ferrets exposed to smoke alone than in all other groups. Levels were [approximately]300 and 500% of the controls, respectively. However, smoke-elevated total p53 and phosphorylated p53 were markedly attenuated by both doses of lycopene. p21[superscript Waf1/Cip1], Bax-1, and cleaved caspase 3 were substantially decreased, whereas cyclin D1 and proliferating cellular nuclear antigen (PCNA) were increased in ferrets exposed to smoke alone. Lycopene prevented smoke-induced changes in p21[superscript Waf1/Cip1], Bax-1, cleaved caspase 3, cyclin D1, and PCNA in a dose-dependent fashion. These data indicate that lycopene may prevent smoke exposure-induced changes in p53, p53 phosphorylation, p53 target genes, cell proliferation, and apoptosis in the gastric mucosa of ferrets.
Descriptors: ferrets, animal disease models, smoking habit, lycopene, dietary supplements, protein phosphorylation, cell proliferation, apoptosis, human health, gastric mucosa, cigarettes, gastric cancer, human diseases, chemoprevention, gene expression, proliferating cell nuclear antigen, cyclins, animal proteins.

Maher, J.A. and J. DeStefano (2004). The ferret: An animal model to study influenza virus. Lab Animal 33(9): 50-53. ISSN: 0093-7355.
NAL Call Number: QL55.A1L33
Abstract: There has been much critical influenza research conducted in a little-known laboratory animal--the ferret. The authors review some of these findings, discuss the reasons the ferret often becomes a model for influenza infection, and compare the ferret with other animal models.
Descriptors: ferrets, animal models, orthomyxoviridae, influenza, literature review.

Maines, T.R., L.M. Chen, Y. Matsuoka, H. Chen, T. Rowe, J. Ortin, A. Falcon, T.H. Nguyen, l.Q. Mai, E.R. Sedyaningsih, S. Harun, T.M. Tumpey, R.O. Donis, N.J. Cox, K. Subbarao, and J.M. Katz (2006). Lack of transmission of H5N1 avian-human reassortant influenza viruses in a ferret model. Proceedings of the National Academy of Sciences of the United States of America 103(32): 12121-12126. ISSN: 0027-8424.
Abstract: Avian influenza A H5N1 viruses continue to spread globally among birds, resulting in occasional transmission of virus from infected poultry to humans. Probable human-to-human transmission has been documented rarely, but H5N1 viruses have not yet acquired the ability to transmit efficiently among humans, an essential property of a pandemic virus. The pandemics of 1957 and 1968 were caused by avian-human reassortant influenza viruses that had acquired human virus-like receptor binding properties. However, the relative contribution of human internal protein genes or other molecular changes to the efficient transmission of influenza viruses among humans remains poorly understood. Here, we report on a comparative ferret model that parallels the efficient transmission of H3N2 human viruses and the poor transmission of H5N1 avian viruses in humans. In this model, an H3N2 reassortant virus with avian virus internal protein genes exhibited efficient replication but inefficient transmission, whereas H5N1 reassortant viruses with four or six human virus internal protein genes exhibited reduced replication and no transmission. These findings indicate that the human virus H3N2 surface protein genes alone did not confer efficient transmissibility and that acquisition of human virus internal protein genes alone was insufficient for this 1997 H5N1 virus to develop pandemic capabilities, even after serial passages in a mammalian host. These results highlight the complexity of the genetic basis of influenza virus transmissibility and suggest that H5N1 viruses may require further adaptation to acquire this essential pandemic trait.
Descriptors: ferrets virology, influenza A virus, H5N1, metabolism, human transmission, human virology, reassortant viruses, metabolism, disease models, virus replication.

Mann, A., A.C. Marriott, S. Balasingam, R. Lambkin, J.S. Oxford, and N.J. Dimmock (2006). Interfering vaccine (defective interfering influenza A virus) protects ferrets from influenza, and allows them to develop solid immunity to reinfection. Vaccine 24(20): 4290-4296. ISSN: 0264-410X.
NAL Call Number: QR189.V32
Abstract: Defective interfering (DI) virus RNAs result from major deletions in full-length viral RNAs that occur spontaneously during de novo RNA synthesis. These RNAs are packaged into virions that are by definition non-infectious, and are delivered to cells normally targeted by the virion. DI RNAs can only replicate with the aid of a coinfecting infectious helper virus, but the small size of DI RNA allows more copies of it to be made than of its full-length counterpart, so the cell produces defective virions in place of infectious progeny. In line with this scenario, the expected lethal disease in an influenza A virus-mouse model is made subclinical by administration of DI virus, but animals develop solid immunity to the infecting virus. Hence DI virus has been called an 'interfering vaccine'. Because interfering vaccine acts intracellularly and at a molecular level, it should be effective against all influenza A viruses regardless of subtype. Here we have used the ferret, widely acknowledged as the best model for human influenza. We show that an interfering vaccine with defective RNAs from an H3N8 virus almost completely abolished clinical disease caused by A/Sydney/5/97 (H3N2), with abrogation of fever and significant reductions in clinical signs of illness. Animals recovered fully and were solidly immune to reinfection, in line with the view that treatment converts the otherwise virulent disease into a subclinical and immunizing infection.
Descriptors: influenza vaccines, administration, dosage, influenza virus A immunology, ferrets, mice, orthomyxoviridae infections, immunology.

Mishin, V.P., M.S. Nedyalkova, F.G. Hayden, and L.V. Gubareva (2005). Protection afforded by intranasal immunization with the neuraminidase-lacking mutant of influenza A virus in a ferret model. Vaccine 23(22): 2922-2927. ISSN: 0264-410X.
NAL Call Number: QR189.V32
Abstract: Protective efficacy of the intranasal immunization with the neuraminidase (NA)-deficient mutant of the influenza A virus was investigated in ferrets. Despite the highly attenuated replication in vivo, the mutant completely protected the animals against the wild type virus challenge. When challenge was done with antigenic drift variants, significant reductions in the viral titers, inflammatory cell counts, and protein concentrations were observed in the nasal washes of the immunized animals. The genetically engineered NA-deficient mutant also protected animals against the challenge and induced humoral immune response against the foreign protein that replaced the NA. We conclude that the NA as antigen is dispensable in the live attenuated influenza virus vaccine and that the NA-lacking mutant can be used as a virus vector.
Descriptors: ferrets, influenza A virus, vaccine administration, neuraminidase genetics, orthomyxoviridae infections, intranasal administration, virus enzymology, genetics, animal models.

Odekunle, A. and T.I. Chinnah (2003). Brainstem origin of duodenal vagal preganglionic parasympathetic neurons. A WGA-HRP study in the ferret (Mustela Putorius Furo), a human model. West Indian Medical Journal 52(4): 267-272. ISSN: 0043-3144.
Abstract: The projections of vagal brainstem neurons to the duodenal segment of the gastrointestinal tract were studied in the ferret using the WGA-HRP neurohistochemical technique. Fourteen adult ferrets with weights ranging from 800 gm to 1500 gm were used for the study. The muscular wall of the duodenum of six ferrets was injected with 0.1 ml of 5% WGA-HRP in 0.5 M sodium chloride. The eight remaining ferrets were used as controls. Two of these had injections of 0.1 ml normal saline into the muscular wall of the duodenum. The second set of two ferrets was injected with 0.1 ml of 5% WGA-HRP in buffer after bilateral truncal vagotomy. The third set of two ferrets received intraperitoneal injection of 0.1 ml of 5% WGA-HRP while, in the last set, the tracer was injected into the hepatic portal vein. Following the injections, the ferrets were allowed to survive for 48-72 hours after which each ferret was perfused transcardially first with normal saline followed by a fixative containing 1% paraformaldehyde and 1.25% glutaraldehyde in 0.1 M phosphate buffer, pH 7.4 at room temperature and finally with 10% buffered sucrose at 4 degrees C. Transverse serial frozen sections of the brainstem were then taken and processed for WGA-HRP neurohistochemistry and were analyzed under light and dark-field illuminations. The analyses of the sections taken from the six ferrets injected with WGA-HRP revealed neurons labelled with the tracer in the dorsal motor nucleus of the vagus nerve (DMNV). Sections taken from the control ferrets did not reveal any WGA-HRP labelled neurons in the brainstem.
Descriptors: ferrets, preganglionic autonomic fibers, duodenum innervation, molecular probes, parasympathetic nervous system, vagus nerve, animal models, neural pathways.

Olsen, A.K. (2005). Ilderen som forsogsdyr. [Ferrets as experimental animals]. Dansk Veterinaertidsskrift 88(6): 8-9. ISSN: 0106-6854.
Descriptors: ferrets, research, brain, disease models, laboratory animals, stomach ulcers, vaccination, viruses.
Language of Text: Danish.

Peltola, V.T., K.L. Boyd, J.L. McAuley, J.E. Rehg, and J.A. McCullers (2006). Bacterial sinusitis and otitis media following influenza virus infection in ferrets. Infection and Immunity 74(5): 2562-2567. ISSN: 1098-5522.
NAL Call Number: QR1.I57
Abstract: Streptococcus pneumoniae is the leading cause of otitis media, sinusitis, and pneumonia. Many of these infections result from antecedent influenza virus infections. In this study we sought to determine whether the frequency and character of secondary pneumococcal infections differed depending on the strain of influenza virus that preceded bacterial challenge. In young ferrets infected with influenza virus and then challenged with pneumococcus, influenza viruses of any subtype increased bacterial colonization of the nasopharynx. Nine out of 10 ferrets infected with H3N2 subtype influenza A viruses developed either sinusitis or otitis media, while only 1 out of 11 ferrets infected with either an H1N1 influenza A virus or an influenza B virus did so. These data may partially explain why bacterial complication rates are higher during seasons when H3N2 viruses predominate. This animal model will be useful for further study of the mechanisms that underlie viral-bacterial synergism.
Descriptors: ferrets, bacterial infection, virus infection, sinusitis, pneumonia, viral-bacterial synergism.

Raila, J., C. Gomez, and F.J. Schweigert (2002). The ferret as a model for vitamin A metabolism in carnivores. Journal of Nutrition 132(6 Suppl 2): 1787s-1789s. ISSN: 0022-3166.
NAL Call Number: 389.8 J82
Descriptors: ferret metabolism, vitamin A, diet, kidney metabolism, liver metabolism, retinol binding proteins, animal models.

Ter Meulen, J., A.B.H. Bakker, E.N. Van Den Brink, G.J. Weverling, B.E.E. Martina, B.L. Haagmans, T. Kuiken, J. De Kruif, W. Preiser, W. Spaan, H.R. Gelderblom, J. Goudsmit, and A.D.M.E. Osterhaus (2004). Human monoclonal antibody as prophylaxis for sars coronavirus infection in ferrets. Lancet 363(9427): 2139-2141. ISSN: 0099-5355.
Descriptors: ferrets, SARS infection, coronavirus infection, human monoclonal antibody, prophylaxis, severe acute reapiratory syndrome, animal model.

von Messling, V., C. Springfeld, P. Devaux, and R. Cattaneo (2003). A ferret model of canine distemper virus virulence and immunosuppression. Journal of Virology 77(23): 12579-12591. ISSN: 0022-538X.
NAL Call Number: QR360.J6
Abstract: Canine distemper virus (CDV) infects many carnivores, including ferrets and dogs, and is the member of the Morbillivirus genus most easily amenable to experimentation in a homologous small-animal system. To gain insights into the determinants of CDV pathogenesis, we isolated a strain highly virulent for ferrets by repeated passaging in these animals. Sequence comparison of the genome of this strain with that of its highly attenuated precursor revealed 19 mutations distributed almost evenly in the six genes. We then recovered a virus from a cDNA copy of the virulent CDV strain's consensus sequence by using a modified reverse genetics system based on B cells. We infected ferrets with this virus and showed that it fully retained virulence as measured by the timing of rash appearance, disease onset, and death. Body temperature, leukocyte number, lymphocyte proliferation activity, and cell-associated viremia also had similar kinetics. We then addressed the question of the relative importance of the envelope and other viral constituents for virulence. Viruses in which the envelope genes (matrix, fusion, and hemagglutinin) of the virulent strain were combined with the other genes of the attenuated strain caused severe rash and fever even if the disease onset was delayed. Viruses in which the nucleocapsid, polymerase, and phosphoprotein genes (coding also for the V and C proteins) of the virulent strain were combined with the envelope genes of the attenuated strain caused milder signs of disease. Thus, virulence-inducing mutations have accumulated throughout the genome.
Descriptors: ferrets, animal disease models, distemper virus, canine pathogenicity, immunosuppression, b lymphocytes immunology, DNA, canine genetics, vero cells, virulence genetics.

von Messling, V., C. Springfeld, P. Devaux, and R. Cattaneo (2003). A ferret model of canine distemper virus virulence and immunosuppression. Journal of Virology 77(23): 12579-12591. ISSN: 0022-538X.
NAL Call Number: QR360.J6
Descriptors: ferret, animal model, canine distemper, virulence, immunosuppression, Morbillivirus.

Wang, X.D. (2005). Can smoke-exposed ferrets be utilized to unravel the mechanisms of action of lycopene. Journal of Nutrition 135(8): 2053S-2056S. ISSN: 0022-3166.
NAL Call Number: 389.8 J82
Descriptors: tomato products, lycopene, anticarcinogenic activity, lung cancer, ferrets, animal models, smoking habit, mechanism of action, dosage, metabolites, blood chemistry, lungs, cell proliferation, epidemiology.
Notes: In the special section: "Promises and perils of lycopene/tomato supplementation and cancer prevention." Presented at a conference held February 17-18, 2005, Bethesda, Maryland.

Wolf, G. (2002). The effect of low and high doses of beta-carotene and exposure to cigarette smoking on the lungs of ferrets. Nutrition Reviews 60(3): 88-90. ISSN: 0029-6643.
NAL Call Number: 389.8 N953
Abstract: When the diets of ferrets were supplemented with large (pharmacologic) daily doses of beta-carotene (BC) for 6 months, the levels of retinoic acid and the retinoic acid receptor beta declined significantly in lung tissues. Indicators of cell proliferation (c-jun and c-fos proteins and others) increased. Histologic observations showed that feeding high doses of BC resulted in keratinized squamous metaplasia in the lung tissues. When high-doses of BC were combined with daily exposure to cigarette smoke, the BC effects were greatly accentuated. These results may lead to an explanation of the increased incidence of lung cancer in two large independent epidemiologic studies of smokers in which pharmacologic doses of BC were given.
Descriptors: beta carotene, tobacco smoking, passive smoking, lungs, animal tissues, receptors, vitamin supplements, ferrets, literature reviews, lung tissues.

Woods, J.B., C.K. Schmitt, S.C. Darnell, K.C. Meysick, and A. O'Brien (2002). Ferrets as a model system for renal disease secondary to intestinal infection with Escherichia coli O157:H7 and other Shiga toxin-producing E. coli. Journal of Infectious Diseases 185(4): 550-554. ISSN: 0022-1899.
NAL Call Number: 448.8 J821
Abstract: Ferrets were evaluated as a possible small animal model for the development of colitis and/or signs of the hemolytic uremic syndrome after oral infection with Escherichia coli O157:H7 or other Shiga toxin--producing E. coli (STEC). Ferrets treated with streptomycin (Stm) had higher counts of E. coli O157:H7 strain 86-24 Stm-resistant (Stm(r)) or O91:H21 strain B2F1 Stm(r) in their stools than non--Stm-treated animals. None of the animals displayed evidence of colitis, but Stm-treated animals fed strain 86-24 Stm(r) exhibited weight loss significantly greater than that exhibited by ferrets fed an isogenic mutant negative for the adhesin intimin. Moreover, 11 (23%) of the 47 Stm-treated ferrets inoculated with 86-24 Stm(r) or B2F1 Stm(r) developed hematuria and/or histological damage to glomeruli or thrombocytopenia, compared with 0 of 14 uninfected control animals receiving Stm in water. Thus, the ferret may serve as a model for renal disease secondary to intestinal infection with STEC.
Descriptors: ferrets, animal disease models, Escherichia coli infections, Escherichia coli o157 pathogenicity, Escherichia coli proteins, intestinal diseases, kidney diseases, shiga toxin, intestinal diseases, streptomycin .

Zitzow, L.A., T. Rowe, T. Morken, W.J. Shieh, S. Zaki, and J.M. Katz (2002). Pathogenesis of avian influenza A (H5N1) viruses in ferrets. Journal of Virology 76(9): 4420-4429. ISSN: 0022-538X.
NAL Call Number: QR360.J6
Abstract: Highly pathogenic avian influenza A H5N1 viruses caused outbreaks of disease in domestic poultry and humans in Hong Kong in 1997. Direct transmission of the H5N1 viruses from birds to humans resulted in 18 documented cases of respiratory illness, including six deaths. Here we evaluated two of the avian H5N1 viruses isolated from humans for their ability to replicate and cause disease in outbred ferrets. A/Hong Kong/483/97 virus was isolated from a fatal case and was highly pathogenic in the BALB/c mouse model, whereas A/Hong Kong/486/97 virus was isolated from a case with mild illness and exhibited a low-pathogenicity phenotype in mice. Ferrets infected intranasally with 10(7) 50% egg infectious doses (EID(50)) of either H5N1 virus exhibited severe lethargy, fever, weight loss, transient lymphopenia, and replication in the upper and lower respiratory tract, as well as multiple systemic organs, including the brain. Gastrointestinal symptoms were seen in some animals. In contrast, weight loss and severe lethargy were not noted in ferrets infected with 10(7) EID(50) of two recent human H3N2 viruses, although these viruses were also isolated from the brains, but not other extrapulmonary organs, of infected animals. The results demonstrate that both H5N1 viruses were highly virulent in the outbred ferret model, unlike the differential pathogenicity documented in inbred BALB/c mice. We propose the ferret as an alternative model system for the study of these highly pathogenic avian viruses.
Descriptors: disease models, ferrets, influenza physiopathology, influenza A virus, avian pathogenicity, adolescent, child, influenza pathology and virology, lung pathology and virology, virulence, virus replication.

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