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Vitamin B 12 (cobalamin or Cbl) functions as a cofactor in two important enzymatic processes in human cells, and life is not sustainable without it. B 12 is obtained from food and travels from the stomach, through the intestine, and into the bloodstream by three B 12 -transporting proteins: salivary haptocorrin (HC), gastric intrinsic factor, and transcobalamin (TC), which all bind B 12 with high affinity and require proteolytic degradation to liberate Cbl. After intracellular delivery of dietary B 12 , Cbl in the aquo/hydroxocobalamin form can coordinate various nucleophiles, for example, GSH, giving rise to glutathionylcobalamin (GSCbl), a naturally occurring form of vitamin B 12 . Currently, there is no data showing whether GSCbl is recognized and transported in the human body. Our crystallographic data shows for the first time the complex between a vitamin B 12 transporter and GSCbl, which compared to aquo/hydroxocobalamin, binds TC equally well. Furthermore, sequence analysis and structural comparisons show that TC recognizes and transports GSCbl and that the residues involved are conserved among TCs from different organisms. Interestingly, haptocorrin and intrinsic factor are not structurally tailored to bind GSCbl. This study provides new insights into the interactions between TC and Cbl., Competing Interests: Conflict of interests The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The ability of Timm's sulphide silver method to stain zincergic terminal fields has made it a useful neuromorphological marker. Beyond its roles in zinc-signalling and neuromodulation, zinc is involved in the pathophysiology of ischemic stroke, epilepsy, degenerative diseases and neuropsychiatric conditions. In addition to visualising zincergic terminal fields, the method also labels transition metals in neuronal perikarya and glial cells. To provide a benchmark reference for planning and interpretation of experimental investigations of zinc-related phenomena in rat brains, we have established a comprehensive repository of serial microscopic images from a historical collection of coronally, horizontally and sagittally oriented rat brain sections stained with Timm's method. Adjacent Nissl-stained sections showing cytoarchitecture, and customised atlas overlays from a three-dimensional rat brain reference atlas registered to each section image are included for spatial reference and guiding identification of anatomical boundaries. The Timm-Nissl atlas, available from EBRAINS, enables experimental researchers to navigate normal rat brain material in three planes and investigate the spatial distribution and density of zincergic terminal fields across the entire brain., (© 2023. The Author(s).)

The destruction of alveolar bone is a crucial manifestation of severe chronic periodontitis, which stem cell-based bioengineered therapies are expected to cure. Therefore, a cost-effective, reproducible, quantifiability and easier to administrate animal model that mimics human periodontitis is of great importance for further endeavor. In this study, we created periodontitis rat models in silk ligation group, bone defect group and bone defect/silk ligation group, respectively. Obvious periodontal inflammation but slight alveolar bone resorption was observed in the ligation group, while surgical trauma was not robust enough to continually worsen the constructed bone defect area in the bone defect group. In the bone defect/ligature group, significant and stable periodontal inflammation was the most enduring with similar evolving pathological patterns of human periodontitis. It also exhibited enhanced clinical similarity and confirmed its superiority in quantitativeness. The present rat model is the first study to reproduce a pathological process similar to human periodontitis with reliable stability and repeatability, manifesting a priority to previous methods. Day 9-12 is the best time for reproducing severe periodontitis syndromes with vertical bone resorption in this model., (© 2022. The Author(s), under exclusive licence to The Society of The Nippon Dental University.)

Background: Intravascular delivery of nanoparticles for theranostic application permits direct interaction of nanoparticles and vascular cells. Since vascular smooth muscle cells (VSMCs), the major components of the vascular wall, are constantly subjected to mechanical stimulation from hemodynamic influence, we asked whether cyclic strain may modulate internalization of magnetic nanoparticles (MNPs) by cultured VSMCs., Methods: Cyclic strain (1 Hz and 10%) was applied with Flexcell system in cultured VSMCs from rats, with cell-associated MNPs (MNP cell ) determined by a colorimetric iron assay. Transmission and scanning electron microscopy were used for morphology studies. Confocal microscopy was used to demonstrate distribution of actin assembly in VSMCs., Results: Incubation of poly(acrylic acid) (PAA)-coated MNPs with VSMCs for 4 h induced microvilli formation and MNP internalization. Application of cyclic strain for 4-12 h significantly reduced MNP cell by up to 65% ( p < 0.05), which was associated with blunted microvilli and reduced vesicle size/cell, but not vesicle numbers/cell. Confocal microscopy demonstrated that both cyclic strain and fibronectin coating of the culture plate reduced internalized MNPs, which were co-localized with vinculin. Furthermore, cytochalasin D reduced MNP cell , suggesting a role of actin polymerization in MNP uptake by VSMCs; however, a myosin II ATPase inhibitor, blebbistatin, exhibited no effect. Cyclic strain also attenuated uptake of PAA-MNPs by LN-229 cells and uptake of poly-L-lysine-coated MNPs by VSMCs., Conclusion: In such a dynamic milieu, cyclic strain may impede cellular internalization of nanocarriers, which spares the nanocarriers and augments their delivery to the target site in the lumen of vessels or outside of the circulatory system., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Tsai et al.)

Whereas much research has been conducted on rats in their roles as pests and laboratory animal models, little is known about rats in their role as companion animals. However, rats have become the third most common companion animal admitted to the British Columbia Society for the Prevention of Cruelty to Animals (BC SPCA) shelter system after cats and dogs. This paper analyses 5 years of province-wide rat admission and outcome data (n = 3,392) at the BC SPCA. Most rats that entered BC SPCA shelters were white, sexually intact, and pups less than 6 months old. Rats were mostly relinquished by their owners, and the most common surrender reasons were due to owner-related issues and housing issues. Reasons for euthanasia were primarily poor health and neonatal age. A multiple linear regression model found that rats that were either senior, albino, unhealthy, seized by humane officers, or born onsite tended to stay longer in shelters (F[12, 1466] = 9.565, p < .001, adjusted R2 = .06). Time to adoption for albino rats was 79% longer than for white rats. These findings help us understand the preferences of rat adopters and why the rat-human relationship may fail. Results may also be useful to improve the quality of life for pet rats by identifying programs to reduce their length of stay in animal shelters. Finally, our study highlights new questions for welfare research in an understudied companion animal-the pet rat., Competing Interests: The authors have declared that no competing interests exist.

Time course of changes in neuroinflammatory processes in the dorsal and ventral hippocampus was studied during the early period after lateral fluid percussion-induced neocortical traumatic brain injury (TBI) in the ipsilateral and contralateral hemispheres. In the ipsilateral hippocampus, neuroinflammation (increase in expression of pro-inflammatory cytokines) was evident from day 1 after TBI and ceased by day 14, while in the contralateral hippocampus, it was mainly limited to the dorsal part on day 1. TBI induced an increase in hippocampal corticosterone level on day 3 bilaterally and an accumulation of Il1b on day 1 in the ipsilateral hippocampus. Activation of microglia was observed from day 7 in different hippocampal areas of both hemispheres. Neuronal cell loss was detected in the ipsilateral dentate gyrus on day 3 and extended to the contralateral hippocampus by day 7 after TBI. The data suggest that TBI results in distant hippocampal damage (delayed neurodegeneration in the dentate gyrus and microglia proliferation in both the ipsilateral and contralateral hippocampus), the time course of this damage being different from that of the neuroinflammatory response., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Aims: Animal models of human disease are a key component of translational hepatology research, yet there is no consensus on which model is optimal for NAFLD., Approach and Results: We generated a database of 3,920 rodent models of NAFLD. Study designs were highly heterogeneous, and therefore, few models had been cited more than once. Analysis of genetic models supported the current evidence for the role of adipose dysfunction and suggested a role for innate immunity in the progression of NAFLD. We identified that high-fat, high-fructose diets most closely recapitulate the human phenotype of NAFLD. There was substantial variability in the nomenclature of animal models: a consensus on terminology of specialist diets is needed. More broadly, this analysis demonstrates the variability in preclinical study design, which has wider implications for the reproducibility of in vivo experiments both in the field of hepatology and beyond., Conclusions: This systematic analysis provides a framework for phenotypic assessment of NAFLD models and highlights the need for increased standardization and replication., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: To date, despite the substantial literature investigating how rats prefer to be kept in captivity, no research has been conducted to assess the housing, husbandry and health of pet rats., Methods: To better understand the United Kingdom's pet rat population and the welfare issues they face, we conducted an online survey of pet rat owners. The survey included questions about the owner and their opinions about pet rats, and about their rats' health, husbandry and housing., Results: The results, from 677 complete responses, highlighted areas of rat care that were "good", "bad" and "ugly" (i.e. likely to be highly detrimental to welfare). The good was that many rats were provided with a social companion and enrichment; the bad was that we could not be certain whether rats had a sufficiently nutritious diet or sufficient opportunities to explore or adequate nesting substrate; and the ugly included cases of exposure of rats to predator species within the home and a generally high prevalence of disease., Conclusions: We conclude that there is much cause for concern about the welfare of pet rats in the United Kingdom., (© 2021 The Authors. Veterinary Record published by John Wiley & Sons Ltd on behalf of British Veterinary Association.)

Rodents including rats are reservoir of several pathogens capable of affecting human health. In this study, faecal and different organ specimens from free-living Norway rats (Rattus norvegicus) (N = 18) and faecal samples from laboratory rodents (rats N = 21 and mice N = 20) collected from different geographic areas in Hungary between 2017 and 2020 were investigated by viral metagenomics and conventional RT-PCR methods. The complete genome of three different RNA viruses, rat astrovirus, rat norovirus and rat hepevirus were characterized and analysed in detail. Rat norovirus was detected in faecal (17.6%, 3/17) and kidney (7.1%, 1/14) samples; rat astrovirus in faecal (23.5%, 4/17) and spleen (13.3%, 2/15) samples, and rat hepevirus in 43% to 67% the faecal, liver, kidney, lung, heart, muscle, brain and blood samples from Norway rats, respectively. Rat norovirus was also identifiable in 5% (1/21) of laboratory rats and rat astrovirus in 40% (8/20) of faecal samples from laboratory mice. Co-infections were found in 28% (5/18) wild Norway rats. The highest RNA viral load of astrovirus (1.81 × 10 8 copy/g) and norovirus (3.49 × 10 7 copy/g) were measured in faecal samples; while the highest RNA viral load of hepevirus (1.16 × 10 9 copy/g) was found in liver samples of Norway rats, respectively. This study confirms the wide geographic distribution and high prevalence of astrovirus, norovirus and hepevirus among wild rats in Hungary with confirmation of different organ involvement of as well as the detection of norovirus and astrovirus in laboratory rats and mice, respectively. This finding further strengthens the role of rodents in the spread of viral pathogens especially infecting human., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Pregnancy diagnosis and embryo counting are important end points in reproductive, developmental biology and toxicology studies. The purpose of the present study was to assess the feasibility and efficacy of magnetic resonance imaging (MRI) for early pregnancy diagnosis and embryo counting in the laboratory rat. Female Wistar rats were subjected to whole-body MRI scanning using a 1.5T MRI scanner, employing a isotropic T2-weighted 3D short-tau inversion recovery sequence from day 8 to day 12 post coitum (pc) or without prior mating, under general anaesthesia for pregnancy diagnosis and embryo counting. MRI examination was followed by laparotomy and visual inspection of the uterus to verify MRI findings. By day 8 pc, uterine bulges, characteristic of pregnancy, were depicted as oval-shaped structures of high intensity signal. By day 10 pc, embryonic vesicles were detected at the medial side of the uterine bulges. Pregnancy was diagnosed with 0% false-negative diagnosis and 100% accuracy by day 11 pc, while embryos were counted with 100% accuracy by day 12 pc. In conclusion, MRI proved to be a feasible and reliable non-invasive imaging method of early pregnancy diagnosis and embryo counting in the laboratory rat.

Article 23(2) of the European Union Directive 2010/63/EU, which regulates welfare provisions for animals used for scientific purposes, requires that staff involved in the care and use of animals for scientific purposes be adequately educated and trained before they undertake any such work. However, the nature and extent of such training is not stipulated in the Directive. To facilitate Member States in fulfilling their education and training obligations, the European Commission developed a common Education and Training Framework, which was endorsed by the Member States Competent Authorities. An Education & Training Platform for Laboratory Animal Science (ETPLAS) Working Group was recently established to develop further guidance to the Learning Outcomes in the Framework, with the objective to clarify the levels of knowledge and understanding required by trainees, and to provide the criteria by which these Learning Outcomes should be assessed. Using the Framework document as a starting point, assessment criteria for the Learning Outcomes of the modules required for Function A persons (carrying out procedures on animals) for rats, mice and zebrafish were created with sufficient detail to enable trainees, providers and assessors to appreciate the level of knowledge, understanding and skills required to pass each module. Adoption and utilization of this document by training providers and accrediting or approving bodies will harmonize introductory education and training for those involved in the care and use of animals for scientific purposes within the European Union, promote mutual recognition of training within and between Member States and therefore free movement of personnel.

The laboratory rat continues to be the model of choice for many studies of physiology, behavior, and complex human diseases. Cells of the mononuclear phagocyte system (MPS; monocytes, macrophages, and dendritic cells) are abundant residents in every tissue in the body and regulate postnatal development, homeostasis, and innate and acquired immunity. Recruitment and proliferation of MPS cells is an essential component of both initiation and resolution of inflammation. The large majority of current knowledge of MPS biology is derived from studies of inbred mice, but advances in technology and resources have eliminated many of the advantages of the mouse as a model. In this article, we review the tools available and the current state of knowledge of development, homeostasis, regulation, and diversity within the MPS of the rat., (Copyright © 2021 by The American Association of Immunologists, Inc.)

Nephroblastoma is an embryonal tumour that has rarely been reported in laboratory rats. In this case report, a large nephroblastoma with peritoneal seeding was found during necropsy in an 11-month-old, female, Sprague Dawley rat. The rat had a history of indirect exposure to nano-TiO 2 (titanium dioxide nanoparticles) during maternal gestation. A firm mass in the upper right abdominal quadrant was palpated. Four weeks later, the animal quickly declined. Nephroblastoma was confirmed by histopathology. Only one rat developed nephroblastoma among the ten littermates. Nephroblastomas in Sprague Dawley rats are typically spontaneous tumours with non-malignant mesenchymal elements. The capability to induce a nephroblastoma with nano-TiO 2 is less likely in this case., (© 2020 The Authors Veterinary Medicine and Science Published by John Wiley & Sons Ltd.)

Domestic rats are the principal reservoir for urban leptospirosis. However, few studies have identified infestation markers in slums and evaluated their predictivity for leptospirosis risk. We compared households with leptospirosis cases in Salvador, Brazil between 2007 and 2009 and their neighbors using a case control design, surveying for rodent infestation signs and environmental characteristics. With the 2007-2008 data, a conditional logistic regression modeling identified the peridomiciliar presence of rodent burrows (OR, 3.30; 95% CI, 1.50-7.26), rat feces (2.86; 1.24-6.59), runs (2.57; 1.06-6.22), households bordering abandoned houses (2.48; 1.04-6.02), and unplastered walls (2.22; 1.02-6.02) as risk factors and developed a predictive score for leptospirosis. With an independent data set from 2009, a receiver operating characteristic (ROC) curve analysis evaluated the prediction score performance, with the area under the curve being 0.70 (95% CI, 0.64-0.76) for score development and 0.71 (0.65-0.79) for validation. Results indicate that high proportions of urban slum households are infested with R. norvegicus. The score performed well when identifying high-risk households within slums. These findings need confirmation in other urban centers, but suggest that community-based screening for rodent infestation can allow to target rodent and environmental control measures in populations at highest risk for leptospirosis., Competing Interests: The authors have declared no competing interest.

In November 2013, a fatal encephalomyocarditis virus (EMCV) case in a captive African elephant ( Loxodonta africana ) occurred at the Réserve Africaine de Sigean, a zoo in the south of France. Here we report the molecular characterization of the EMCV strains isolated from samples collected from the dead elephant and from 3 rats ( Rattus rattus ) captured in the zoo at the same time. The EMCV infection was confirmed by reverse-transcription real-time PCR (RT-rtPCR) and genome sequencing. Complete genome sequencing and sequence alignment indicated that the elephant's EMCV strain was 98.1-99.9% identical to the rat EMCV isolates at the nucleotide sequence level. Phylogenetic analysis of the ORF, P1, VP1, and 3D sequences revealed that the elephant and rat strains clustered into lineage A of the EMCV 1 group. To our knowledge, molecular characterization of EMCV in France and Europe has not been reported previously in a captive elephant. The full genome analyses of EMCV isolated from an elephant and rats in the same outbreak emphasizes the role of rodents in EMCV introduction and circulation in zoos.

Introduction: We recently developed an inducible model of dysphagia using intralingual injection of cholera toxin B conjugated to saporin (CTB-SAP) to cause death of hypoglossal neurons. In this study we aimed to evaluate tongue morphology and ultrastructural changes in hypoglossal neurons and nerve fibers in this model., Methods: Tissues were collected from 20 rats (10 control and 10 CTB-SAP animals) on day 9 post-injection. Tongues were weighed, measured, and analyzed for microscopic changes using laminin immunohistochemistry. Hypoglossal neurons and axons were examined using transmission electron microscopy., Results: The cross-sectional area of myofibers in the posterior genioglossus was decreased in CTB-SAP-injected rats. Degenerative changes were observed in both the cell bodies and distal axons of hypoglossal neurons., Discussion: Preliminary results indicate this model may have translational application to a variety of neurodegenerative diseases resulting in tongue dysfunction and associated dysphagia., (© 2020 Wiley Periodicals LLC.)

Background: Rodents are one of the most dangerous reservoirs and carriers of infectious diseases. Gradually, rats have become predominant in cities, sometimes staying in close vicinity to humans, pets, and other animals. Consequently, they tend to increase the transmission risk of pathogens., Case Description: Here, we report an original case of bacterial pneumonia in a street rat ( Rattus norvegicus ). The rat was found dead on a street in the chief town of Marseille (France) after being run over by a car. The necropsy of the corpse revealed generalized granulomatous pneumonia in almost all the pulmonary lobes. Lung lesions and predominantly multiple fibro-inflammatory areas are presumably the witness of an infectious etiology. Bacterial isolation was carried out from lung tissues. Colonies were identified by MALDI-TOF MS and confirmed by 16S rRNA sequencing. The following bacteria were identified: Staphylococcus cohnii , Bordetella bronchiseptica , Bordetella parapertussi, Corynebacterium glucuronolyticum , Pelistega suis and Rodentibacter rarus . Based on the histopathological diagnosis and the avoidance approach, the most likely etiological agent of pneumonia is therefore R. rarus , a little-known Pasteurellales bacterium that is closely related to Rodentibacter pneumotropicus., Conclusion: These data emphasize the severity of R. rarus infection in rodents. Thus, pointing out a potential risk for other animals (dogs, cats, and birds), as well as humans. The health monitoring program for rodents and rabbits pasteurellosis should now include R. rarus . Therefore, the pathological effect of the Rodentibacter species and/or strains needs to be better explored., Competing Interests: The authors declare that there is no conflict of interest.

Introduction: Our aim was to assess key muscle imaging and contractility parameters in the Duchenne muscular dystrophy (DMD) rat model (Dmd-KO rat), which have not yet been characterized sufficiently., Methods: We performed in-vivo magnetic resonance imaging (MRI) for thigh and leg muscles, and performed hematoxylin and eosin (H&E) staining and in-vivo muscle contractility testing in specific hindlimb muscles., Results: MRI prior to testing muscle contractility revealed multiple, unevenly distributed focal hyperintensities in the Dmd-KO rat quadriceps and tibialis anterior muscles. H&E staining showed corresponding areas of inflammation and ongoing regeneration. In-vivo contractile testing showed maximal force generated by Dmd-KO muscles was significantly lower, and susceptibility to injury was ~ two-fold greater in the Dmd-KO rats compared to wild-type (WT) rats., Discussion: Together, the MRI findings, histological findings, and the low strength and high susceptibility to injury in muscles support use of the Dmd-KO rat as an animal model of DMD., (© 2020 Wiley Periodicals LLC.)

Duchenne muscular dystrophy (DMD) is X-linked recessive myopathy caused by mutations in the dystrophin gene. Although conventional treatments have improved their prognosis, inevitable progressive cardiomyopathy is still the leading cause of death in patients with DMD. To explore novel therapeutic options, a suitable animal model with heart involvement has been warranted.We have generated a rat model with an out-of-frame mutation in the dystrophin gene using CRISPR/Cas9 genome editing (DMD rats). The aim of this study was to evaluate their cardiac functions and pathologies to provide baseline data for future experiments developing treatment options for DMD.In comparison with age-matched wild rats, 6-month-old DMD rats showed no significant differences by echocardiographic evaluations. However, 10-month-old DMD rats showed significant deterioration in left ventricular (LV) fractional shortening (P = 0.024), and in tissue Doppler peak systolic velocity (Sa) at the LV lateral wall (P = 0.041) as well as at the right ventricular (RV) free-wall (P = 0.004). These functional findings were consistent with the fibrotic distributions by histological analysis.Although the cardiac phenotype was milder than anticipated, DMD rats showed similar distributions and progression of heart involvement to those of patients with DMD. This animal may be a useful model with which to develop effective drugs and to understand the underlying mechanisms of progressive heart failure in patients with DMD.

Animal models are in constant development to benefit scientific research. Rheumatoid arthritis (RA) is considered a very complex disease due to its complicated pathogenesis, and patients with rheumatic disease around the world are still unable to obtain effective, simple and curable treatment. In order to obtain a clear insight into the pathogenesis of RA, a rat model was established based on the concept of Bi syndrome in Traditional Chinese Medicine by simulating the conditions of RA as much as possible via the change in the physical conditions wind, damp, cold and heat (WDCH). For the first time, a new WDCH-induced RA model in female rats was successfully established and evaluated by body-weight change, paw swelling, blood cells analysis, spleen and thymus coefficients, autoantibodies and serum cytokine changes and histopathology. This model is characterised by its objectivity, no exogenous induction, short modelling time, extremely elevated expression level of autoantibodies and obvious histopathological change. The establishment of such a new model may provide more benefits in the research of the pathogenesis of RA.

The laboratory rat has been used for a long time as the model of choice in several biomedical disciplines. Numerous inbred strains have been isolated, displaying a wide range of phenotypes and providing many models of human traits and diseases. Rat genome mapping and genomics was considerably developed in the last decades. The availability of these resources has stimulated numerous studies aimed at discovering causal disease genes by positional identification. Numerous rat genes have now been identified that underlie monogenic or complex diseases and remarkably, these results have been translated to the human in a significant proportion of cases, leading to the identification of novel human disease susceptibility genes, helping in studying the mechanisms underlying the pathological abnormalities and also suggesting new therapeutic approaches. In addition, reverse genetic tools have been developed. Several genome-editing methods were introduced to generate targeted mutations in genes the function of which could be clarified in this manner [generally these are knockout mutations]. Furthermore, even when the human gene causing a disease had been identified without resorting to a rat model, mutated rat strains (in particular KO strains) were created to analyze the gene function and the disease pathogenesis. Today, over 350 rat genes have been identified as underlying diseases or playing a key role in critical biological processes that are altered in diseases, thereby providing a rich resource of disease models. This article is an update of the progress made in this research and provides the reader with an inventory of these disease genes, a significant number of which have similar effects in rat and humans.

Purpose: N-methyl-N-nitrosourea (MNU) is an alkylating toxicant with potent mutagenic ability. This study was designed to induce apoptosis in lens epithelial cells (LECs) and corneal endothelial cells (CECs) via MNU administration. We sought to build ocular disease models of cataract and corneal endothelial decompensation., Methods: MNU was delivered into the intraperitoneal cavities of neonatal rats and the anterior chambers of adult rabbits. The MNU-treated animals were then subjected to a series of functional and morphological analyses at various time points., Results: MNU treatment induced pervasive apoptosis of LECs and CECs. These effects were dose and time dependent. Mature cataracts were found in neonatal rats 3 weeks after MNU treatment. Histological analysis revealed that MNU toxicity induced swelling, vacuolation, and liquefaction in lens fibers of MNU-treated rats. Pentacam examination showed that the average density of rat lens increased significantly after MNU administration. Terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) analysis showed pervasive apoptotic staining in the lenses of MNU-treated rats. In rabbit eyes, intracameral treatment with MNU induced corneal edema and significantly increased central corneal thickness, which peaked at P14. Morphological and immunohistochemical analysis showed that CECs were effectively ablated in the MNU-treated rabbits. The expression of 8-OHdG increased significantly in the cornea of MNU-treated rabbits, compared with vehicle-treated controls., Conclusions: MNU is sufficient to induce ocular cell apoptosis in animal models. These models of MNU-induced cataract and corneal endothelial decompensation represent valuable tools for efforts to develop relevant therapies.

Objective: Positron emission tomography (PET) is a non-invasive technique measuring quantification of physiological and biochemical processes in the living organism. However, there are many considerations including anesthesia and fasting to acquire small animal imaging. We aimed to evaluate the effects of anesthesia and fasting of rats in dopamine transporter (DAT) imaging acquisition., Methods: Male Sprague Dawley (SD) rats aged 7 weeks and weighing 180-260 g were used in this study. Rats were randomly divided by 4 groups. Group A was kept under anesthesia for 40 min and fasted over 12 h. Group B was only fasted over 12 h. Group C was only kept under anesthesia for 40 min. Group D was neither kept under anesthesia nor fasted over 12 h. PET scans were started at 40 min after 18 F-FP-CIT injection and obtained for 20 min. Volumes-of-interest for striatum and extrastriatal area were used for 18 F-FP-CIT PET analysis. Cerebellum was considered as a reference region. Specific binding ratio (SBR) was calculated as follows: [(uptake of target-uptake of cerebellum)]/(uptake of cerebellum)., Results: SBR without fasting and anesthesia (group D) was significantly lower than those of other groups (vs group A, p = 0.0004; vs group B, p = 0.0377; vs group C, p = 0.0134). However, SBRs of extrastriatal area (p = 0.5120) were not affected by fasting and anesthesia., Conclusions: In conclusion, the SBR of striatum was increased after anesthesia by isoflurane and fasting. When designing an experiment using DAT imaging, the effects of isoflurane and fasting should be considered.

Introduction: Vitamin K (VK) is a co-factor in the post-translational gamma glutamic carboxylation of Gla-proteins. VK-dependent coagulation factors are carboxylated in the liver by VK1. Osteocalcin and Matrix-Gla protein (MGP) are carboxylated in extrahepatic tissues by VK2. A model of VK deficiency would be suitable for studying extrahepatic Gla-proteins provided that severe bleeding is prevented., Aim: The aim of this work was to adapt an established protocol of vascular calcification by warfarin-induced inactivation of MGP as a calcification inhibitor, in an attempt to create a broader state of subclinical VK deficiency and to verify its safety., Materials and Methods: Two consecutive experiments, each lasting 4 weeks, were required to modify the dosing schedule of warfa-rin and VK1 and to adapt it to the Wistar rats used. The original high doses of warfarin used initially had to be halved and the protective dose of VK1 to be doubled, in order to avoid treatment-induced hemorrhagic deaths. The second experiment aimed to confirm the efficacy and safety of the modified doses. To verify the VK deficiency, blood vessels were examined histologically for calcium deposits and serum osteocalcin levels were mea-sured., Results: The original dosing schedule induced VK deficiency, manifested by arterial calcifications and dramatic changes in carboxyl-ated and uncarboxylated osteocalcin. The modified dosing regimen caused similar vascular calcification and no bleeding., Conclusion: The modified protocol of carefully balanced warfarin and VK1 doses is an effective and safe way to induce subclinical VK deficiency that can be implemented to investigate VK-dependent proteins like osteocalcin., (This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Bartonella spp. are vector-borne pathogens transmitted to humans via blood-sucking arthropods. Rodents such as the black rat (Rattus rattus) and Norway rat (R. norvegicus) are thought to be the main reservoirs. An infection with rodent-associated Bartonella spp. may cause severe symptoms in humans such as endocarditis and neuroretinitis. The current knowledge of Bartonella prevalence in rats from western Europe is scarce., Methods: Rats and a few other rodent by-catches were trapped in the context of a rodenticide resistance study at different sites in Flanders, Belgium. During dissection, biometric data were collected, and spleen tissues were taken. DNA was extracted from spleen samples and tested for Bartonella spp. by conventional generic polymerase chain reaction (PCR). To determine the Bartonella species, a selected number of amplicons were sequenced and compared with GenBank entries., Results: In total, 1123 rodents were trapped. The predominate species was R. norvegicus (99.64%). Other rodents trapped included: two water voles (Arvicola amphibius, 0.18%); one colour rat (R. norvegicus forma domestica, 0.09%); and one muskrat (Ondatra zibethicus, 0.09%). PCR analysis of 1097 rodents resulted in 410 (37.37%, 95% CI: 34.50-40.31%) Bartonella spp. DNA-positive samples. Bartonella tribocorum (94.68%, 95% CI: 88.02-98.25%) was the most frequently detected Bartonella species, followed by B. grahamii (3.19%, 95% CI: 0.66-9.04%) and B. doshiae (1.06%, 95% CI: 0.03-5.79%). An uncultured Bartonella species occurred in one water vole (1.06%, 95% CI: 0.03-5.79%). There was a significantly higher Bartonella prevalence in older rats compared to juveniles and a significant difference in Bartonella prevalence concerning the localisation of trapping sites. In contrast, there was no statistically significant difference in Bartonella prevalence regarding sex, degree of urbanisation and season., Conclusions: Based on the high prevalence found, we conclude that the Norway rat seems to be a key reservoir host for zoonotic B. tribocorum in Belgium.

Plague is a low incidence flea-borne zoonosis that is often fatal if treatment is delayed or inadequate. Outbreaks occur sporadically and human cases are often preceded by epizootics among rodents. Early recognition of epizootics coupled with appropriate prevention measures should reduce plague morbidity and mortality. For nearly a century, the flea index (a measure of fleas per host) has been used as a measure of risk for epizootic spread and human plague case occurrence, yet the practicality and effectiveness of its use in surveillance programs has not been evaluated rigorously. We sought to determine whether long-term monitoring of the Xenopsylla flea index on hut-dwelling rats in sentinel villages in the plague-endemic West Nile region of Uganda accurately predicted plague occurrence in the surrounding parish. Based on observations spanning ~6 yr, we showed that on average, the Xenopsylla flea index increased prior to the start of the annual plague season and tended to be higher in years when plague activity was reported in humans or rodents compared with years when it was not. However, this labor-intensive effort had limited spatial coverage and was a poor predictor of plague activity within sentinel parishes., (Published by Oxford University Press on behalf of Entomological Society of America 2019.)

Based on the contribution of the endocannabinoid system to the pathophysiology of schizophrenia, the primary pro-psychotic ingredient of Cannabis sativa, Δ-9-tetrahydrocannabinol (Δ-9-THC), is used in preclinical as well as clinical research to mimic schizophrenia-like symptoms. While it is common to administer lipid-based formulations of Δ-9-THC in human studies orally, intraperitoneal injections of water-based solutions are used in animal models. Because of the poor water solubility of Δ-9-THC, solubilizers such as ethanol and/or emulsifiers are needed for these preparations. In order to test whether a lipid-based solvent would be superior over a water-based vehicle in rats, we compared the effects on locomotor activity and prepulse inhibition (PPI) of the acoustic startle reaction, as well as pharmacokinetic data obtained from rats' serum and brain tissue samples. Up to 50 mg/kg Δ-9-THC in the lipid-based formulation was not able to induce any behavioral alterations, while already 5 mg/kg of the water-based Δ-9-THC preparation significantly reduced locomotor activity. This also induced a small but significant PPI reduction, which was prepulse intensity dependent. Interestingly, the reflexive motor response to the startle stimulus was not affected by the water-based Δ-9-THC solution. Analysis of serum and brain Δ-9-THC levels by high-performance liquid chromatography/mass spectrometry revealed that although the final concentration reached in the brain was comparable for both pharmaceutical preparations, the water-based formulation achieved a faster kinetic. We, therefore, conclude that the slope of the Δ-9-THC concentration-time curve and the resulting cannabinoid receptor type 1 activation per time unit are responsible for the induction of behavioral alterations., (© 2019 Society for the Study of Addiction.)

The systemic administration of low reserpine (RES) doses (0.1-1.0 mg/kg) has been proposed as a valuable rat model for the study of non-motor symptoms of Parkinson's disease (PD). Here, we investigated the temporal-dependent effects of RES (1 mg/kg, s.c.) on short-term memory and locomotion, as well as, the levels of dopamine, serotonin and its metabolites in the striatum, hippocampus and prefrontal cortex at 3, 24 or 72 h after RES administration. RES administrations resulted in social and object recognition memory impairment and increased dopamine turnover in the striatum, without changes in the rat spontaneous locomotor activity, 3 h after RES administration. Altogether, these results provide new insights for the use of RES administration as an experimental design for the study of PD non-motor symptoms in rats., Competing Interests: Declaration of Competing Interest The authors have no financial or personal conflict of interest related to this work., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Ulcers in patients with diabetic neuropathy in their feet are quite common but should be differentiated from the distinctive but rare ulceration resulting from rat bites in these insensate feet. We describe and analyze the features of rat bites in 2 patients with diabetic neuropathy in their feet and highlight 8 clinical features that should raise suspicion and alert the clinician to this possibility., Methods: We describe and analyze the features of rat bites in 2 patients with diabetic neuropathy in their feet and highlight the distinctive clinical features of this condition., Results: The following features were noted: 1) blood on bed sheets on waking; 2) painless, nonsuppurating ulceration; 3) multiple ulcers that are linear, sharp, or with serrated edges; 4) varying depths within the ulcer; 5) sudden onset (was not noted the day before but found in morning); 6) ulcers not contiguous; 7) often bilateral; and 8) the sole of the foot is not involved. Early recognition and prompt treatment resulted in digit and limb salvage., Conclusions: We describe and analyze the features of rat bites in 2 patients with diabetic neuropathy in their feet and highlight 8 clinical features that should raise suspicion and alert the clinician to this possibility., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Genetic quality assurance (QA), including genetic monitoring (GeMo) of inbred strains and background characterization (BC) of genetically altered (GA) animal models, should be an essential component of any QA programme in laboratory animal facilities. Genetic quality control is as important for ensuring the validity of the animal model as health and microbiology monitoring are. It should be required that studies using laboratory rodents, mainly mice and rats, utilize genetically defined animals. This paper, presented by the FELASA Working Group on Genetic Quality Assurance and Genetic Monitoring of Laboratory Murines, describes the objectives of and available methods for genetic QA programmes in rodent facilities. The main goals of any genetic QA programme are: (a) to verify the authenticity and uniformity of inbred stains and substrains, thus ensuring a genetically reliable colony maintenance; (b) to detect possible genetic contamination; and (c) to precisely describe the genetic composition of GA lines. While this publication focuses mainly on mouse and rat genetic QA, the principles will apply to other rodent species some of which are briefly mentioned within the context of inbred and outbred stocks.

Hymenolepidid cestodes of synanthropic rodents represent a risk for public health. In order to describe the occurrence of hymenolepidids in children and the role of rodents as a potential source of infection, we conducted a morphological and molecular survey on cestodes in two rural villages from Yucatan, Mexico. One hundred and thirty-five stool samples from children (64 from Paraíso and 71 from Xkalakdzonot), 233 Mus musculus (159 from Paraíso and 74 from Xkalakdzonot) and 125 Rattus rattus (7 from Paraíso and 118 from Xkalakdzonot) were analyzed for the presence of cestodes. Three hymenolepidid species were identified morphologically: Hymenolepis nana in 7.8% of children from Paraíso, Hymenolepis microstoma in 4.4% of M. musculus from Paraíso and Hymenolepis diminuta in 15.3% of R. rattus from Xkalakdzonot. The molecular characterization and phylogenetic analysis based on mitochondrial cytochrome c subunit 1 (CO1) gene and ribosomal internal transcribed spacer 1 (ITS1) region, confirmed the identity of the three cestodes isolated from Yucatan. Phylogeny of the CO1 gene identified intraspecific genetic differences within H. nana ranging from 0 to 5%, in H. microstoma from 0 to 0.4%, and in H. diminuta ranged from 0 to 6.5% which suggests, the presence of complex species within H. nana and H. diminuta infecting humans and rodents, as reported by other authors. Based on the morphological and molecular results, and the epidemiological evidence, infections with H. nana suggest a non-zoonotic transmission; however, the presence of H. microstoma and H. diminuta in synanthropic rodents serve as a possible source for human infection., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Scents and odours characterize some microbes when grown in the laboratory, and experienced clinicians can diagnose patients with some infectious diseases based on their smell. Animal sniffing is an innate behaviour, and animals' olfactory acuity is used for detecting people, weapons, bombs, narcotics and food., Objectives: We briefly summarized current knowledge regarding the use of sniffing animals to diagnose some infectious diseases and the potential use of scent-based diagnostic instruments in microbiology., Sources: Information was sought through PubMed and extracted from peer-reviewed literature published between January 2000 and September 2019 and from reliable online news. The search terms 'odour', 'scent', 'bacteria', 'diagnostics', 'tuberculosis', 'malaria' and 'volatile compounds' were used., Content: Four major areas of using sniffing animals are summarized. Dogs have been used to reliably detect stool associated with toxigenic Clostridioides difficile and for surveillance. Dogs showed high sensitivity and moderate specificity for detecting urinary tract infections in comparison to culture, especially for Escherichia coli. African giant pouched rats showed superiority for diagnosing tuberculosis over microscopy, but inferiority to culture/molecular methods. Several approaches for detecting malaria by analysing host skin odour or exhaled breath have been explored successfully. Some microbial infections produce specific volatile organic compounds (VOCs), which can be analysed by spectrometry, metabolomics or other analytical approaches to replace animal sniffing., Implications: The results of sniffing animal studies are fascinating, and animal sniffing can provide intermediate diagnostic solutions for some infectious diseases. Lack of reproducibility, and cost of animal training and housing are major drawbacks for wider implementation of sniffing animals. The ultimate goal is to understand the biological background of this animal ability and to characterize the specific VOCs that animals are recognizing. VOC identification, improvement of odour sampling methods and development of point-of-care instruments could allow implementation of scent-based tests for major human pathogens., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Animal models of stroke play a crucial role in determining the pathophysiology of stroke progression and assessment of any new therapeutic approaches. Transient middle cerebral artery occlusion (tMCAo) in rodent models are the most common site-specific type of ischemia because of their relevance to the clinical setting. Compared with the intraluminal filament technique for inducing tMCAo, the transfemoral approach using endovascular wires is relatively a new technique METHODS: Here we present the use of commercially available wires used for neuro-endovascular surgical procedures to induce tMCAo in rats via a transfemoral approach. We used male Wistar rats in four groups to assess the effect of occlusion time (1 vs. 2 hours) and the wire type (PT2 TM 0.014″ vs. TransendTM EX, 0.014″, Boston Scientific, MA, USA). Infarct volume, edema, neurological deficits, and pro-inflammatory/anti-inflammatory blood biomarkers were used as outcome measures., Results: We observed a significant effect of the wire type on the infarct volume (p value = 0.0096) where infarcts were slightly larger in the PT2 wiregroups. However, the occlusion time had no significant effect on infarct volume, even though the interaction between wire-type * occlusion-time was significant (p value = 0.024). Also, the amount of edema and blood pro-inflammatory/anti-inflammatory biomarkers were not statistically different among the wire-type and occlusion-time groups., Conclusions: The choice of appropriate endovascular wire should probably be the focus of the study design instead of the occlusion time when planning an experiment. The transfemoral approach using endovascular wires for inducing tMCAo in rats provides a more consistent outcome with fewer complications compared with suture filament models.

The genus Bartonella (Family: Bartonellaceae ; Order: Rhizobiales; Class: Alphaproteobacteria) comprises facultative intracellular Gram-negative, haemotropic, slow-growing, vector-borne bacteria. Wild rodents and their fleas harbor a great diversity of species and strains of the genus Bartonella , including several zoonotic ones. This genetic diversity coupled with a fastidious nature of the organism results in a taxonomic challenge that has led to a massive collection of uncharacterized strains. Here, we report the genomic and phenotypic characterization of two strains, members of the genus Bartonella (namely Tel Aviv and OE 1-1), isolated from Rattus rattus rats and Synosternus cleopatrae fleas, respectively. Scanning electron microscopy revealed rod-shaped bacteria with polar pili, lengths ranging from 1.0 to 2.0 µm and widths ranging from 0.3 to 0.6 µm. OE 1-1 and Tel Aviv strains contained one single chromosome of 2.16 and 2.23 Mbp and one plasmid of 29.0 and 41.5 Kbp, with average DNA G+C contents of 38.16 and 38.47 mol%, respectively. These strains presented an average nucleotide identity (ANI) of 89.9 %. Bartonella elizabethae was found to be the closest phylogenetic relative of both strains (ANI=90.9-93.6 %). The major fatty acids identified in both strains were C 18:1 ω7 c , C 18 : 0 and C 16 : 0 . They differ from B. elizabethae in their C 17 : 0 and C 15 : 0 compositions. Both strains are strictly capnophilic and their biochemical profiles resembled those of species of the genus Bartonella with validly published names, whereas differences in arylamidase activities partially assisted in their speciation. Genomic and phenotypic differences demonstrate that OE 1-1 and Tel Aviv strains represent novel individual species, closely related to B. elizabethae , for which we propose the names Bartonella kosoyi sp. nov. and Bartonella krasnovii sp. nov.

Rodents serve as amplifiers of Salmonella infections in poultry flocks and can serve as a source of Salmonella contamination in the environment even after thorough cleaning and disinfection. This study aims to determine the dynamics of Salmonella occurrence in rodents and its relation to Salmonella contamination in the layer farm environment, including air dusts and eggs. From 2008 to 2017, roof rats ( Rattus rattus ), environmental swabs, air dusts, and eggs were collected from an intensive commercial layer farm in East Japan and were tested for Salmonella spp. using standard procedures. In roof rat samples, the Salmonella isolation rate was reached at 10% (95% confidence interval [CI] 8.1-21.9) in which Salmonella Corvallis, Salmonella Infantis, Salmonella Potsdam, and Salmonella Mbandaka were the frequent isolates from the cecal portion of the intestines. On the other hand, the prevalence rate of Salmonella in environmental swabs was at 5.1% (95% CI 2.2-7.4) while air dusts were at 0.9% (95% CI 0.2-1.8). It was observed that the prevalence of predominant Salmonella serotypes shifted over time; in roof rats, it was noted that Salmonella Potsdam gradually replaced Salmonella Infantis. In environmental swabs and eggs, Salmonella Corvallis and Salmonella Potsdam increased significantly while Salmonella Infantis became less frequent. In air dusts, Salmonella Corvallis was observed to decrease and Salmonella Potsdam became more common. Based on our findings, the role of roof rats in the epidemiology of Salmonella in layer farms was expanded from being a reservoir and an amplifier host into a shifting vessel of the most predominant serotypes.

Clinical studies have shown that schizophrenia is accompanied by hypoalgesia. Accordingly, we have previously reported that a chronic schizophrenia-related rat substrain (Wisket) showed decreased acute heat pain sensitivity. The aim of the present study was to determine the mechanical pain sensitivity and the effects of opioid ligands in a chronic osteoarthritic pain model generated using Wisket rats. Our previous molecular biological studies indicated that the impairment in opioid and cannabinoid receptor functions observed in these animals did not explain their altered pain sensitivity. Therefore, we aimed to investigate another endogenous antinociceptive system, i.e., the oxytocinergic system (which is also implicated in schizophrenia) via the determination the brain-region specific oxytocin receptor mRNA expression in Wisket rats. Osteoarthritis was induced in male adult control Wistar rats without any interventions and in Wisket rats after juvenile social isolation and ketamine treatment. The degree of allodynia and the effects of systemic morphine or intrathecal endomorphin-1 administration were determined. Furthermore, the expression of the oxytocin receptor mRNA was assessed in different brain structures (prefrontal cortex, striatum, diencephalon, brainstem, and olfactory bulb). A lower degree of allodynia was observed in the Wisket group compared with control animals 1 and 2 weeks after the induction of osteoarthritis, which was accompanied by a comparable degree of edema. Systemically or intrathecally applied opioids caused similar time-response curves in both groups, with apparently shorter effects in Wisket animals. The expression of the oxytocin receptor mRNA was lower in most of the brain regions (with the exception of the diencephalon) investigated in Wisket rats vs. the control animals. In summary, both acute and chronic hypoalgesia (as nonspecific symptoms in patients with schizophrenia) can be simulated in Wisket animals as endophenotypes despite the impairment of the endogenous antinociceptive systems evaluated. Thus, this model might be an appropriate tool for further investigation of the molecular basis of altered pain perception in schizophrenia., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The use of effective regimens for mitigating pain remain underutilized in research rodents despite the general acceptance of both the ethical imperative and regulatory requirements intended to maximize animal welfare. Factors contributing to this gap between the need for and the actual use of analgesia include lack of sufficient evidence-based data on effective regimens, under-dosing due to labor required to dose analgesics at appropriate intervals, concerns that the use of analgesics may impact study outcomes, and beliefs that rodents recover quickly from invasive procedures and as such do not need analgesics. Fundamentally, any discussion of clinical management of pain in rodents must recognize that nociceptive pathways and pain signaling mechanisms are highly conserved across mammalian species, and that central processing of pain is largely equivalent in rodents and other larger research species such as dogs, cats, or primates. Other obstacles to effective pain management in rodents have been the lack of objective, science-driven data on pain assessment, and the availability of appropriate pharmacological tools for pain mitigation. To address this deficit, we have reviewed and summarized the available publications on pain management in rats, mice and guinea pigs. Different drug classes and specific pharmacokinetic profiles, recommended dosages, and routes of administration are discussed, and updated recommendations are provided. Nonpharmacologic tools for increasing the comfort and wellbeing of research animals are also discussed. The potential adverse effects of analgesics are also reviewed. While gaps still exist in our understanding of clinical pain management in rodents, effective pharmacologic and nonpharmacologic strategies are available that can and should be used to provide analgesia while minimizing adverse effects. The key to effective clinical management of pain is thoughtful planning that incorporates study needs and veterinary guidance, knowledge of the pharmacokinetics and mechanisms of action of drugs being considered, careful attention to individual differences, and establishing an institutional culture that commits to pain management for all species as a central component of animal welfare.

Objective: Patulous eustachian tube (PET) is currently treated using a variety of conservative or surgical approaches. To further elucidate the pathology of PET and to establish new therapies, the development of an animal model is necessary. The objective of this study was to develop a highly reproducible and sustainable rat model of PET by mandibular nerve resection., Methods: Sixteen rats underwent mandibular nerve resection. Following an external incision, the main trunk of the mandibular nerve at the foramen ovale was identified in the pterygoid fossa, and its branches were resected. This surgery was performed on the right side, with the unoperated left side used as the control. To determine eustachian tube (ET) function, passive opening pressure (POP) was measured using inflation method up to Week 16 post-surgery. Changes in POP were statistically compared to the preoperative level on the operated and control sides. In addition, specimens of the ET and its surrounding tissue at Week 16 post-surgery were prepared for morphological evaluation in eight rats., Results: On the control side, POP did not significantly decrease across the 16 weeks post-surgery compared to the preoperative level. In contrast, on the operated side, POP was significantly decreased at Week 2 and continued to be lower than the preoperative level until at least Week 16 post-surgery. POP dropped 10% or more on the operated side examined in thirteen rats. Histologically, the medial pterygoid muscle was atrophied on the operated side mainly., Conclusion: Mandibular nerve resection in rats may be an effective method for generating an animal model of PET. It was suggested that this rat model may be useful for verifying new treatments for PET., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This overview provides a brief summary of the complex interactions that link sleep, pain, and analgesic medications. Sleep scientists and clinicians are well aware of these relationships and understand that maintaining healthy pain-free subjects in a stable environment is essential to generating interpretable data and valid conclusions. However, these concepts and the data that support bidirectional interactions between sleep and pain may be less known to those who are not sleep scientists yet need such information to protect and advance both animal wellbeing and research validity (for example, veterinarians, IACUC members). Abundant human evidence supports the disruptive effect of pain and the modulatory effects of analgesic drugs on sleep; however, analgesic drugs can alter both sleep and the electroencephalogram, which is the primary objective measure for identifying sleep and evaluating sleep properties in both humans and animals. Consideration of the modulatory and interactive relationships of sleep, pain, and analgesic medications is essential to designing and conducting valid and reproducible sleep research using animal subjects.

The surgical stress response and resulting physiologic changes can lead to postoperative complications and negatively impact animal welfare. Although appropriate pain management is crucial to reduce the pain and stress response to surgery, analgesic choice can significantly affect bone and wound healing. This review aims to summarize data from rat and mouse studies and to provide recommendations for integrating analgesia into orthopedic and wound healing models in these species. Data from other species, such as humans, rabbits and other rodents, is included, where available. From these data, we conclude that for orthopedic surgical models, opioids, local anesthetics and dissociative agents have minimal impact on fracture healing; cyclooxygenase 2 (COX2) selective nonsteroidal antiinflammatory drugs (NSAID) may be used in the shortterm; and steroids should be avoided. For wound healing models, short-term systemic or topical opioids have negligible impact on wound healing; NSAID or local anesthetics may be used short-term; and systemic steroids should be avoided. Alternative analgesics such as tramadol, gabapentin, ketamine, and acetaminophen warrant consideration and further evaluation for both orthopedic and wound healing models. In all cases, researchers and veterinarians should work together to determine the appropriate analgesic plan to minimize pain, as well as to minimize unwanted effects on the orthopedic and wound healing models themselves.

Sepsis is a multifaceted host response to infection that dramatically affects patient outcomes and the cost of health care. Animal models are necessary to replicate the complexity and heterogeneity of clinical sepsis. However, these models entail a high risk of pain and distress due to tissue trauma, inflammation, endotoxin-mediated hyperalgesia, and other mechanisms. Several recent studies and initiatives address the need to improve the welfare of animals through analgesics and standardize the models used in preclinical sepsis research. Ultimately, the goal is to provide high-fidelity, humane animal models that better replicate the clinical course of sepsis, to provide more effective translation and advance therapeutic discovery. The purpose of this review is to discuss the current understanding of the roles of pain and analgesia in rodent models of sepsis. The current definitions of sepsis along with an overview of pain in human sepsis are described. Finally, welfare concerns associated with animal models of sepsis and the most recent considerations for relief of pain and distress are reviewed.

Mice and rats are valuable and commonly used as models for the study of cancer. The models and methods of experimentation have the potential to cause pain to some degree, and all charged with ensuring animal welfare must determine how to manage it. A commonly posed question, especially from investigators and IACUC, is whether the provision of analgesic agents will render the model invalid. Left untreated, pain is a stressor and has negative consequences, most notably immune system perturbations. In addition, analgesic agents in the opioid and NSAID drug classes exhibit immunomodulatory activity and influence processes such as cell proliferation, apoptosis, and angiogenesis that are important in cancer formation. Therefore, both pain and the agents used to alleviate it have the potential to act as confounding factors in a study. This review article presents data from both human medicine and work with animal models in an attempt to help inform discussions about the withholding of analgesic agents from animals used in cancer studies.

Behavioral neuroscience research incorporates the identical high level of meticulous methodologies and exacting attention to detail as all other scientific disciplines. To achieve maximal rigor and reproducibility of findings, well-trained investigators employ a variety of established best practices. Here we explicate some of the requirements for rigorous experimental design and accurate data analysis in conducting mouse and rat behavioral tests. Novel object recognition is used as an example of a cognitive assay which has been conducted successfully with a range of methods, all based on common principles of appropriate procedures, controls, and statistics. Directors of Rodent Core facilities within Intellectual and Developmental Disabilities Research Centers contribute key aspects of their own novel object recognition protocols, offering insights into essential similarities and less-critical differences. Literature cited in this review article will lead the interested reader to source papers that provide step-by-step protocols which illustrate optimized methods for many standard rodent behavioral assays. Adhering to best practices in behavioral neuroscience will enhance the value of animal models for the multiple goals of understanding biological mechanisms, evaluating consequences of genetic mutations, and discovering efficacious therapeutics., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Minimization and alleviation of stress are generally viewed as desirable aspects of laboratory animal management and use. However, achieving that goal requires an unambiguous and valid measure of stress. Glucocorticoid concentrations are commonly used as a physiologic index of stress. Measurement of glucocorticoids in blood, serum or plasma clearly reflects many types of both acute and chronic stress. However, the rapid rise in concentrations of circulating glucocorticoids that occurs even with relatively simple manipulations such as handling has led to the increased use of fecal glucocorticoid metabolite (FCM) assays, which provide a temporally integrated measure that may allow a more accurate interpretation of chronic stressors. In this review, we consider 3 aspects of glucocorticoids as a measure of stress. First, we discuss the analytic and interpretational pitfalls of using FCM concentrations as an index of stress in mice and rats. Second, we consider evidence that some degree of stress may benefit animals by priming physiologic and behavioral adaptations that render the animals more resilient in the face of stress. Finally, we use 2 situations-social housing and food restriction-to illustrate the concept of hormesis-a biologic phenomenon in which a low dose or intensity of a challenge has a beneficial effect, whereas exposure to high doses or intensities is detrimental.

Background: Methionine is an essential sulfur-containing amino acid. To elucidate the influence of l-methionine on activation of the nuclear factor erythroid 2-related factor 2-antioxidant responsive element (Nrf2-ARE) antioxidant pathway to stimulate the endogenous antioxidant activity for depressing reactive oxygen species (ROS)-derived oxidative stress, male Wistar rats were orally administered l-methionine daily for 14 days., Results: With the intake of l-methionine, Nrf2 was activated by l-methionine through depressing Keap1 and Cul3, resulting in upregulation of ARE-driven antioxidant expression (glutamate cysteine ligase catalytic subunit, glutamate cysteine ligase modulatory subunit, glutathione synthase (GS), catalase (CAT), superoxide dismutase (SOD), heme oxygenase 1, NAD(P)H:quinone oxidoreductase 1, glutathione reductase (GR), glutathione S-transferase (GST), glutathione peroxidase (GPx)) with increasing l-methionine availability. Upon activation of Nrf2, glutathione synthesis was increased through upregulated expression of methionine adenosyltransferase, S-adenosylhomocysteine hydrolase, cystathionine β-synthase, cystathionine γ-lyse, glutamate cysteine ligase (GCL) and GS, while hepatic expressions of methionine sulfoxide reductases (MsrA, MsrB2, MsrB3) and hepatic enzyme activities (CAT, SOD, GCL, GR, GST, GPx) were uniformly stimulated with increasing consumption of l-methionine. As a result, hepatic content of ROS and MDA were effectively reduced by l-methionine intake., Conclusion: The present study demonstrates that methionine availability plays a critical role in activation of the Nrf2-ARE pathway to induce an endogenous antioxidant response for depressing ROS-derived oxidative stress, which is primarily attributed to the stimulation of methionine sulfoxide reductase expression and glutathione synthesis. © 2019 Society of Chemical Industry., (© 2019 Society of Chemical Industry.)