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PubMed1985

Control of ovulation, vaginal estrus, and behavioral receptivity in voles (Microtus).

Rodents of the genus Microtus provide an excellent focus for the study of the effects of environmental and behavioral influences on reproductive physiology. Despite some early reports, there is little definitive evidence of truly spontaneous ovulation in Microtus. Stimuli from copulation with males appear capable of triggering ovulation in all species: the requisite amount of stimulation for ovulation and a functional luteal phase varies with the species. In addition, however, a certain percentage of the females of some, but not all, species ovulate when placed in proximity to males when copulation is presented. There are few reports of regular cycles of cell types in the vaginal smears of Microtus females; the relative preponderance of cornified, nucleated, and leukocytic cells varies with species and conditions. Behavioral receptivity is not invariably correlated with smear type. The complexity of environment-behavior relationships in different species suggests the need for a more comprehensive classification schema for systems of female reproductive physiology and a study of their adaptive significance.

Animals↗

PubMed2000

[A new decision tree method for statistical analysis of quantitative data obtained in toxicity studies on rodents].

Regarding the statistical analysis of the quantitative data obtained in control and dosage groups in toxicity studies, we tried to simplify the decision tree method. In a new decision tree presented in this article, one-way analysis of variance and Kruskal-Wallis nonparametric analysis of variance are excluded from the traditional decision tree: (1) Bartlett's test is used as a test for the equality of k variances: (2) Then, if the k sampled populations have equal variances (p > 0.05 by the Bartlett's test), Dunnett's multiple comparison test is performed: otherwise, Steel's test is used. This new method, which increases the power in some conditions, may serve as an alternative to the traditional decision tree method.

Analysis of Variance↗

PubMed1983

Development of a Babesia rodhaini mouse assay for quality control of the serum component of a bovine babesiosis vaccine.

The rodent babesia, Babesia rodhaini, survived equally well in basal medium containing either 10 per cent rat serum or 10 per cent bovine serum. As a result, a B rodhaini mouse assay is now performed routinely to determine the suitability of batches of bovine serum for use in a commercial Babesia bovis vaccine issued in Australia. Heat inactivation of bovine serum at 56 degrees C for two hours did not affect the survival of either B bovis or B rodhaini.

Animals↗

PubMed1984

Rodent species and strain specificities for sister-chromatid exchange induction and gene mutagenesis effects from ethyl carbamate, ethyl N-hydroxycarbamate, and vinyl carbamate.

Ethyl carbamate (EC) and two related carcinogens, ethyl N-hydroxycarbamate (ENHC) and vinyl carbamate (VC), caused species-specific increases in sister-chromatid exchange (SCE) formation in the bone marrow cells of rodents. Mice exposed to 400 mg/kg of EC had SCE increases of 6-times-baseline, while rats, Chinese hamsters, and golden hamsters showed 3- to 4-times-baseline increases in response to this dose. Lesser, but still significant, differences were found for ENHC and VC; the severest effects consistently occurred in mice. Control bone marrow cell-cycle kinetics among the rodent species were similar. Mouse strains A and C57BL/6, which have high and low susceptibilities to EC induction of lung adenomas, respectively, showed nearly identical levels of SCE induction after in vivo exposure to these carbamates. However, testing of VC, a possible metabolite of EC, in vitro revealed strain-dependent liver enzyme (Aroclor-induced S-9 fraction) capabilities to convert VC to genotoxic products. SCE induction, gene mutation for 6-thioguanine and ouabain resistance, and cytotoxicity in Chinese hamster V79 cells were significantly greater when A strain S-9 enzymes were used as compared with C57BL/6 strain S-9 enzyme preparations. No effect on SCE of reseeding, compared with no reseeding, of VC-treated V79 cells was observed. At a concentration of 25 micrograms/ml, VC caused 6-times-baseline induction of SCE in the presence of A strain S-9 mix and 4-times-baseline induction in the presence of C57BL/6 strain S-9 mix. These in vitro strain-dependent patterns of response are relevant to the current theory that VC may be a proximate carcinogenic metabolite of EC.

Animals↗

PubMed2005

A PYY Q62P variant linked to human obesity.

Peptide YY (PYY) has been implicated in the control of food intake through functional studies in rodents and humans. To investigate whether genetic alterations within this gene result in abnormal weight in humans, we sequenced its coding exons and splice sites in a large cohort of extremely obese [n = 379; average body mass index (BMI), 49.0 kg/m2] and lean (n = 378; average BMI, 19.5 kg/m2) individuals. In total, three rare non-synonymous variants were identified, only one of which, PYY Q62P, exhibited familial segregation with body mass. Through serendipity, previous studies based on cell culture revealed this precise variant to have altered receptor-binding selectivity in vitro. We further show, using mouse peptide injection experiments, that while the wild-type PYY peptide reduces food intake, the mutant PYY 62P had an insignificant effect in reducing food intake in vivo. Taken together, these results are the first to support that rare sequence variants within PYY can influence human susceptibility to obesity.

Amino Acid Sequence↗

PubMedDate not supplied

The value of historical control data-scientific advantages for pathologists, industry and agencies.

Historical control tumor data are useful in the interpretation of long-term rodent carcinogenicity bioassays, especially to assess the occurrence of rare tumors and marginally increased tumor incidences. The major prerequisites to compare historical control data with studies under evaluation are the validity and consistency of the respective databases. The RITA (Registry of Industrial Toxicology Animal-data) database for historical data of tumors and pre-neoplastic lesions collects data according to highly standardized procedures including tissue sampling and trimming, histopathology according to internationally harmonized nomenclature and diagnostic criteria, and peer review. All lesions that are entered are unanimously diagnosed according to IARC (Intermational Agency for Research on Cancer)/WHO criteria. The validity of data is additionally confirmed by a complete peer review performed by a database pathologist. Equivocal diagnoses and selected cases are additionally submitted to a panel of RITA pathologists. In the RITA database, there are currently 10,896 rats from 106 studies with more than 17,604 primary tumors and 16,551 pre-neoplastic lesions. The RITA database for historical control data for Wistar and Sprague Dawley rats as well as for different mouse strains is briefly described. Based upon RITA background data, the survival rate of Wistar rats has been consistent over a period of 10 years. The occurrence of tumor-bearing animals also shows a stable percentage over a decade. Additionally, examples of how historical control data may support carcinogenic risk assessment in cases of rare tumors or marginally increased incidences of tumors and pre-neoplastic lesions are given.

Animals↗

PubMed2002

Characterization of microcirculatory disturbance in a novel model of pancreatic ischemia-reperfusion using intravital fluorescence-microscopy.

INTRODUCTION: Microcirculatory disturbances caused by ischemia-reperfusion injury (IRI) are the crucial hallmarks of pancreatitis following pancreas transplantation. AIMS: To develop a novel rodent model of normothermic in situ ischemia of a pancreatic tail-segment that simulates the clinical situation of pancreas transplantation by flushing the organ via an inserted microcatheter and thus enables selective treatment of the organ via this access. METHODOLOGY: Four experimental groups were investigated (n = 7 Wistar rats/group): sham animals without ischemia and dissection of the pancreas; control animals with dissection of a pancreatic tail segment pedunculated on the splenic vessels and flushing od this segment with saline via a microcatheter; and two groups of animals treated like controls with a pancreatic ischemia time of 1 hour or 2 hours. With use of intravital epifluorescence microscopy, the microcirculatory damage was characterized by investigation of functional capillary density (FCD) and leukocyte adherence in postcapillary venules (LAV) before ischemia and during a reperfusion time of 2 hours. Dry:wet ratio determinations, light microscopy, and electron microscopic investigations were performed to characterize the histologic organ damage. RESULTS: FCD decreased significantly (p < 0.05) 2 hours after reperfusion in the groups of 1-hour (-29.21%) and 2-hour ischemia (-42.73%), in comparison with baseline values. LAV increased significantly (p < 0.05), 4.3- and 5.8-fold, after 1-hour and 2-hour ischemia during the observation time. The histologic damage was similar to posttransplantation pancreatitis in humans 1 hour after reperfusion. In sham and control animals these alterations were not significant. CONCLUSIONS: The rodent in situ model of pancreatic IRI showed standardized microcirculatory damage dependent on the ischemia time. Offering the possibility of selective treatment by the direct artery access to the ischemic pancreatic area, the model enables investigations of questions related to human pancreas transplantation.

Animals↗

PubMed2002

Resistance training increases glucose uptake and transport in rat skeletal muscle.

The aim of this investigation was to determine if resistance training exercise improved glucose uptake and transport in rodent skeletal muscle. Sprague-Dawley rats were assigned to one of the three groups: control (CON), resistance trained (RT) and aerobic exercise trained (AT). Resistance trained rats were placed in a rodent squat apparatus and performed three sets of 10 repetitions at 75% of their one repetition maximum 3 days week-1 for 12 weeks. Aerobic exercise training consisted of running the rats 3 days week-1 for 45 min over a 12-week period on a motor-driven treadmill (32 m min-1, 15% grade). Following the training period, all animals were subjected to hind limb perfusion in the presence of 500 microU mL-1 insulin. Hind limb glucose uptake was similar in the RT (9.91 +/- 0.7 micromol g-1 h-1) and AT (10.23 +/- 1.0 micromol g-1 h-1) animals and significantly greater than control (CON) (6.40 +/- 0.6 micromol g-1 h-1). Rates of 3-O-methyl-d-glucose transport in the RT animals were elevated in the muscles utilized for RT while in the AT animals rates of 3-O-methyl-d-glucose transport were increased in those muscles recruited for running. The increased rates of 3-O-methyl-d-glucose transport in the skeletal muscles of the resistance trained and aerobic exercise trained animals appeared to be, in part, because of an increased GLUT4 protein concentration. These findings suggest that both resistance or aerobic training exercise can improve insulin-stimulated skeletal muscle glucose uptake and transport, but the training adaptations are restricted to the muscles recruited for the exercise performance.

3-O-Methylglucose↗

PubMed2000

Dietary restriction and aging in rhesus monkeys: the University of Wisconsin study.

Dietary restriction (DR) retards aging and extends the maximum lifespan of laboratory mice and rats. To determine whether DR has similar actions in a primate species, we initiated a study in 1989 to investigate the effects of a 30% DR in 30 adult male rhesus monkeys. In 1994, an additional 30 females and 16 males were added to the study. Although the animals are still middle-aged, a few differences have developed between the control and DR animals suggesting that DR may induce physiologic changes in the rhesus monkey similar to those observed in rodents. Fasting basal insulin and glucose concentrations are lower in DR compared to control animals while insulin sensitivity is higher in the restricted animals. DR has also altered circulating LDL in a manner that may inhibit atherogenesis. These results suggest that DR may be slowing some age-related physiologic changes. In addition to measures of glucose and lipid metabolism, the animals are evaluated annually for body composition, energy expenditure, physical activity, hematologic indices, and blood or urinary hormone concentrations. In the next few years, the first animals will reach the average lifespan ( approximately 26 years) of captive rhesus monkeys and it will become possible to determine if DR retards the aging process and extends the lifespan in a primate species.

Aging↗

PubMed2002

In vivo assessment of diabetic lenses using dynamic light scattering.

One of the most threatening aspects of diabetes mellitus is the development of visual impairment. For example, cataracts are 1.6 times more common in people with diabetes than in those without diabetes. Cataract extraction is the only treatment. In many cases, diabetes-related ocular pathologies go undiagnosed until visual function is compromised. This paper compares and contrasts the ocular changes observed using dynamic light scattering (DLS) and conventional ophthalmic techniques during long-term maintenance of the sand rat (Psammomys obesus) on a high caloric diet. P. obesus is a wild rodent in the subfamily Gerbillinae that inhabits the desert areas of the Middle East and Africa. This animal is unique in that it develops mild to moderate obesity, hyperglycemia, pancreatic atrophy, impaired renal function, ketoacidosis, vision loss, and other diabetic complications when it consumes a high caloric diet. In this study, five animals were fed Purina sand rat chow and thus served as normal control animals. Five animals were fed a commercially prepared rodent diet (Purina 5002) consisting of only 4-5% fiber and a grain-based rabbit supplement (BioServe Rabbit Stix Appetite Stimulant) consisting of 50% carbohydrate to provide a high caloric (diabetogenic) diet and thus induce diabetes. Blood samples for the biochemical analyses, DLS, and other optical examinations were obtained on alternate weeks. Our preliminary results have demonstrated subtle changes in the lens of the diabetic sand rats as early as 2 months on a diabetogenic diet. This is an ongoing joint project with Food and Drug Administration and the National Aeronautics and Space Administration. This technique is proving to be a practical, sensitive, noninvasive diagnostic tool useful for the early detection of ocular pathologies and understanding the mechanism of cataract formation.

Animals↗

PubMed1991

Insulin resistance, hyperinsulinemia, hypertriglyceridemia, and hypertension. Parallels between human disease and rodent models.

There is considerable evidence that abnormalities of glucose, insulin, and lipoprotein metabolism occur more frequently in untreated hypertensive patients than in normotensive control subjects. More recently, it has also become apparent that similar metabolic abnormalities occur in rodent models of hypertension. One purpose of this article is to review the experimental data that have led to the above generalizations. The second goal is to address the significance of these findings, which is certainly not clear. For example, it could be argued that the relationship between high blood pressure and the associated metabolic defects is incidental. On the other hand, there is evidence that the changes in glucose, insulin, and lipoprotein metabolism may play a role in the etiology and/or clinical course of patients with high blood pressure. Although it is impossible at this point to definitively choose between these possibilities, an effort is made to marshal the evidence in support of the latter alternative.

Animals↗

PubMed2003

Efficacy of adenoviral p53 delivery with SCH58500 in the intracranial 9l and RG2 models.

Malignant gliomas remain incurable entities that provide fertile ground for experimental therapy. The observation that impaired p53 expression is present in a proportion of these tumors suggests that reconstitution of this ability may impart some degree of tumor control. In this investigation, the 9L and RG2 intracranial rodent tumor models are utilized to assess SCH58500, an adenoviral p53 delivery system. The RG2 tumors demonstrate a greater propensity for transfection with this vector in vitro than the 9L tumors. In vivo, little tumor transfection beyond the immediate area of the needle tract used for direct SCH58500 injection was observed in either tumor type. Intracarotid injection resulted in no tumor transfection. Even at high concentrations of SCH58500 or control virus, injections resulted in no apparent toxicity in terms of weight gain, eating habits or activity in normal animals. The intratumoral administration of SCH58500 enhances the survival of animals with established 9L tumors. Both SCH58500 and its control viral construct not containing the p53 gene enhance survival in animals with RG2 tumors. None of the injected viral constructs caused an alteration in the markers used to detect the character of the white cell infiltrate in either of these tumors. Utilization of SCH58500 provides measurable efficacy in these preclinical brain tumor models without significant toxicity.

Adenoviridae↗

PubMed1986

Induction of cytochrome P-450 and related drug-metabolizing activities in the livers of different rodent species by 2-acetylaminofluorene or by 3-methylcholanthrene.

In general, large differences in the control levels of different cytochrome P-450-catalyzed activities (aminopyrine N-demethylase, benzo(a)pyrene monooxygenase, ethoxyresorufin O-deethylase, ethoxycoumarin O-deethylase and total 2-acetylaminofluorene metabolism and metabolite pattern) and in the inducibility of these activities in different rodent species (rat, hamster, guinea pig and mouse) and sexes were observed. For all the activities measured the lowest levels were observed in untreated rats. With a few minor exceptions, the only species tested in which cytochrome P-450-catalyzed activities were induced by treatment with 2-acetylaminofluorene was the rat. A larger number of the species tested were susceptible to induction by 3-methylcholanthrene. However, this xenobiotic proved also to induce most potently in the rat. There are relatively large differences between the male and female rat both in terms of control cytochrome P-450-catalyzed activities and in the inducibility of these activities by 2-acetylaminofluorene and 3-methylcholanthrene. In general, both of these xenobiotics proved to be more potent inducers in the female than in the male. Thus, it is quite clear that in quantitative terms the hepatic microsomal cytochrome P-450-catalyzed activities and their inducibility by 2-acetylaminofluorene or 3-methylcholanthrene in the male Sprague-Dawley rat are not representative for other rodent species or even for the female of the same species.

2-Acetylaminofluorene↗

PubMed1993

Developmental changes in human gamma-aminobutyric acidA receptor subunit composition.

gamma-Aminobutyric acid (GABA) is the neurotransmitter at most inhibitory synapses in the human central nervous system. The GABAA receptor, a ligand-gated ion channel, is the site of action of benzodiazepines, the most widely prescribed neuroactive drugs. It was recently demonstrated that there are multiple subtypes of GABAA receptors. Studies of rodents have shown that receptor subunits are developmentally controlled. The major alpha subunit of the adult receptor is expressed at low levels before birth. This study, using postmortem human tissue, shows that GABAA receptors are present in significant numbers in the human cerebellum at birth, and the numbers rise threefold by adulthood. Two subtypes of benzodiazepine receptors were detected by binding studies in the neonate, whereas only a single subtype of receptor was detected in the adult cerebellum. Comparison to recombinant human GABAA receptors shows that receptors containing alpha 1 constitute 50% of the receptors at birth and the percentage rises to over 95% by adulthood. In both cerebral cortex and cerebellum, a dramatic rise in alpha 1 messenger RNA was observed during development, suggesting that the complement of GABAA receptors differs in infants and adults. These findings have significant implications for normal neurodevelopment as well as for the understanding and treatment of pathophysiological states such as seizures.

Adolescent↗

PubMed1993

Restoration of the thymus in aging mice by in vivo zinc supplementation.

A multiparametric study of the thymus was performed in normal aging mice (12-15 months old) submitted to a mild oral zinc supplementation during 3-6 months as compared to age-matched control mice. First, this study demonstrated that in rodents, zinc levels are significantly reduced with aging and can be restored to values close to those observed in young animals after 6 months of zinc supplementation. Second, our data showed that oral zinc administration stimulates thymus growth and partially restores the microenvironmental as well as lymphoid compartments of the organ. Regarding thymic endocrine function, a significant increase in thymulin levels and a concomitant decrease in plasma thymulin inhibitors were observed, suggesting that the age-related decline of thymic function might at least partially be due to extrinsic factors, such as zinc deficiency. The total number of thymic lymphocytes was consistently increased, without significant changes in CD4/CD8 defined thymocyte subsets. Finally, structural changes of the thymus epithelium were also detected, including the disappearance of epithelial cysts frequently observed in old animals, reappearance of a normal pattern of the thymic epithelial cell network, and a decrease in the extracellular matrix network. Taken together, these data suggest that aging-related physiological zinc deficiency induces some relevant changes in thymus structure and function which can be partially corrected by a mild oral zinc supplementation.

Administration, Oral↗

PubMed2006

Unacylated as well as acylated ghrelin promotes cell survival and inhibit apoptosis in HIT-T15 pancreatic beta-cells.

Ghrelin is mainly produced by the stomach, although it is expressed in other tissues, including the pancreas. Among its pleiotropic actions, ghrelin prevents the development of diabetes in rats and exerts mitogenic and antiapoptotic effects in different cell types. In addition, a ghrelin-producing epsilon-cell population has been demonstrated in rodent islets, suggesting a direct role in the control of islet cell survival. In this study, we investigated the effect of acylated ghrelin (AG) and unacylated ghrelin (UAG) on cell survival of HIT-T15 pancreatic beta cells. We show that both AG and UAG equally prevented beta cell death induced by serum withdrawal. In addition, both peptides inhibited serum starvation-induced apoptosis. These findings indicate that UAG and AG prevent cell death and apoptosis of pancreatic beta cells. Since only AG, but not UAG, binds the GRLN receptor, a different and as yet unknown receptor is likely involved in these survival mechanisms.

Acetylation↗

PubMed2002

Identification of quantitative trait loci for prepulse inhibition in rats.

INTRODUCTION: Schizophrenia is a common and debilitating psychiatric disorder that is partially under genetic control. Because of difficulties in mapping the genes that influence susceptibility to schizophrenia in humans, there has been substantial interest in mapping genes that control endophenotypes for schizophrenia in both human and rodent populations. Deficient prepulse inhibition (PPI) of the startle response has shown promise as an endophenotype for schizophrenia, as well as several other psychiatric disorders. METHODS: Brown Norway (BN/SsNHsd) and Wistar Kyoto (WKY/lj-cr) rats were used because they show a large, unconfounded difference in PPI. We used interval mapping methods to identify quantitative trait loci (QTL) for PPI in a backcross population. RESULTS: We identified a QTL on chromosome 2 with a LOD score of 3.63 and a suggestive QTL on chromosome 18 with a LOD score of 2.71. CONCLUSIONS: Both of the identified regions contain several candidate genes. Furthermore, the implicated rat chromosomes are syntenic with human chromosomal regions that have been reported to contain QTL for schizophrenia, bipolar disorder, and Tourette's syndrome. These results identify the chromosomal location of gene(s) that modulate an endophenotype for schizophrenia, and other psychiatric disorders, and may provide a shortcut to identifying specific genes and/or biochemical pathways involved in human psychiatric diseases.

Acoustic Stimulation↗

PubMed1990

Fish oil dietary supplementation reduces Ia expression in rat and mouse peritoneal macrophages.

Preliminary studies suggest that administration of fish oil fatty acids may be beneficial in several immunological diseases; therefore, we studied the effect of fish oil dietary supplementation on the expression of Ia in stimulated murine peritoneal macrophages. Rats (n = 19) and mice (n = 27) on standard rodent feeding were separated in experimental (E) and control (C) groups that received fish oil or saline solution, respectively, daily for 4 weeks by esophageal gavage. Cholesterol serum levels were significantly lowered by fish oil (E vs C, P less than 0.01). E and C groups were injected intraperitoneally with Listeria monocytogenes (LM) and peritoneal cells were harvested 4 and 7 days after infection. Decreased expression of Ia induced by LM was found in rats (C = 49.68 +/- 5.09%, E = 16.95 +/- 4.3%, P less than 0.01) and mice (C = 47.38 +/- 7.63%, E = 26.66 +/- 1.92%, P less than 0.01). Animals with a more pronounced depression of serum cholesterol (reduction of 44.04 +/- 1.52% of baseline levels) had more depression of Ia expression (6.47 +/- 1.22%, P less than 0.001 vs control). Reduction of Ia expression was not related to PGE2 production by peritoneal cells. Reduction of Ia expression by fish oil could induce down-regulation of antigen presentation and alloreactivity.

Animals↗