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PubMed2005

MRI detection of early bone metastases in b16 mouse melanoma models.

Bone metastasis causes significant morbidity in cancer patients, including bone pain, pathologic fractures, nerve compression syndrome, and hypercalcemia. Animal models are utilized to study the pathogenesis of skeletal metastases and to evaluate potential therapeutic agents. Previously published methods for imaging bone metastasis in rodent models have focused on identifying advanced stage metastasis using simple X-rays. Here we report MRI as a method for detecting early bone metastases in mouse models in vivo. B16 mouse melanoma cells were injected into the left cardiac ventricle of C57BL/6 mice and magnetic resonance (MR) images were obtained of the left leg following the development of metastatic disease, when tumor associated bone destruction was histologically present but not visible by X-ray. T1 and T2 relaxation times of bone marrow were measured in healthy control mice and B16 melanoma tumor-bearing mice. Mean T2 values for normal marrow were 28 ms (SD 5) and for diseased bone marrow were 41 ms (SD 3). T2 relaxation time of diseased bone marrow is significantly longer than that of normal bone marrow (P < 0.0001) and can be used as a marker of early bone metastases. These studies demonstrate that MR imaging can detect bone marrow metastases in small animals prior to development of cortical bone loss identified by X-ray.

Animals↗
PubMed2001

Superoxide-mediated activation of cardiac fibroblasts by serum factors in hypomagnesemia.

Magnesium deficiency is known to produce myocardial fibrosis in different animal models, but the underlying mechanisms are unclear. However, circulating levels of pro-oxidant and mitogenic factors are reported to be elevated in a rodent model of acute magnesium deficiency, suggesting a role for humoral factors in the pathogenesis of the cardiovascular lesions. Probing the mechanism of cardiac fibrogenesis in magnesium deficiency, the present study furnished evidence that serum from magnesium-deficient rats has a more marked effect than serum from magnesium-sufficient rats on mitogenesis, net collagen production, and superoxide generation in cardiac fibroblasts from young adult rats. The enhanced mitogenic response was abolished by superoxide dismutase and N-acetyl cysteine, showing that it is mediated by superoxide anion. Further, a modest inhibitory effect of the neurokinin-1 receptor antagonist, spantide, suggested that factors acting via neurokinin-1 receptors may partly modulate cardiac fibroblast function in magnesium deficiency. The findings are consistent with the postulation that serum factors may activate cardiac fibroblasts via a superoxide-mediated mechanism and contribute to the fibrogenic response in the heart in magnesium deficiency.

Animals↗
PubMed2005

Emotional learning and glutamate: translational perspectives.

Anxiety disorders are a common focus of clinical concern and certain forms of anxiety may be conceptualized as disorders of emotional learning. Behavior therapies effective in the treatment of anxiety are modeled on extinction training as a means of reducing pathological anxiety. The present understanding of human anxiety has been informed by preclinical research using rodent models to study the acquisition and extinction of fear. Glutamate appears to have a central role in both of these processes. The authors review this literature and discuss novel applications of D-cycloserine, a partial N-methyl-D-aspartate agonist, for the treatment of anxiety.

Animals↗
PubMed2006

End organ effects of high-dose human equivalent methylprednisolone in a spinal cord injury rat model.

STUDY DESIGN: Interventional study. OBJECTIVE: To analyze the histologic effects of high-dose human equivalent methylprednisolone on the pulmonary, cardiac, intestinal, renal, hepatic, and splenic tissues in a spinal cord injury rat model. SUMMARY OF BACKGROUND DATA: There are numerous investigations of various medical interventions for the treatment of acute spinal cord trauma. Currently, the only generally accepted medical intervention in an acute spinal cord trauma is the intravenous administration of high doses of methylprednisolone. Although it has been nearly 2 decades since the first National Acute Spinal Cord Injury Study investigated the role high-dose steroids might play in the treatment of acute spinal cord trauma, controversy still exists regarding the efficacy of this treatment. To our knowledge, no study has examined the role of high-dose methylprednisolone in organ systems other than the spinal cord in an acute spinal cord injury model at the histologic level. This study attempts to characterize end organ histologic response to human dose equivalent (HDE) intravenous methylprednisolone administration in a rodent model of acute spinal cord injury. METHODS: A total of 48 Sprague-Dawley rats were divided equally into control and experimental groups. Each group was subdivided into 6 sets of 4 animals each, according to intervals after injury. Groups 1-6 consisted of animals euthanized at 0, 4, 8, 16, 24, and 48 hours after spinal cord injury. Paraplegia after lower thoracic laminectomy was achieved using a standardized Allen weight drop technique. Within 1 hour of injury, experimental animals were treated with HDE methylprednisolone, infused for 23 hours continuously. Liver, kidney, lung, intestine, spleen, and heart were harvested at variable intervals after injury and prepared for histologic examination. These slides were analyzed with microscopic staining techniques and compared in a blinded manner by a qualified pathologist. RESULTS: Of all the end organs analyzed, the spleens were most affected. Lymphocytic depletion was seen in as little as 4 hours after methylprednisolone infusion and continued until 48 hours. Pulmonary tissues variably showed interstitial congestion and eosinophilic alveolar collections. Intestinal mucosal tissues showed edema and autolyzed mucosa from 16 hours onwards. Cardiac, kidney, and hepatic tissue did not differ significantly from controls. CONCLUSIONS: Histologically, HDE methylprednisolone caused significant splenic lymphocytic depletion changes in as little as 4 hours. This trend of end organ lymphocytopenia continued to progress until 48 hours. Pulmonary eosinophilic infiltrates were seen from 8 until 24 hours. Intestinal mucosal edema and necrosis were seen in samples at 16 hours throughout 48 hours. This study was designed to evaluate end organ changes seen in an animal model of an acute spinal cord injury treated with HDE methylprednisolone. Study animals were infused with HDE methylprednisolone given according to the National Acute Spinal Cord Injury Study II protocol. The kidney, lung, cardiac, intestinal, splenic, and hepatic tissues from the aforementioned animals were then sectioned and analyzed using histologic staining techniques by a qualified pathologist.

Animals↗
PubMed1993

Comparative histopathologic consequences of photothrombotic occlusion of the distal middle cerebral artery in Sprague-Dawley and Wistar rats.

BACKGROUND AND PURPOSE: We have developed a minimally invasive model of photothrombotic occlusion of the distal middle cerebral artery in rats and have evaluated the patterns and features of the resulting histopathologic injury in two normotensive strains. METHODS: Food-deprived male Sprague-Dawley (n = 14) and Wistar (n = 10) rats anesthetized with halothane/nitrous oxide underwent a small craniotomy to expose the right distal middle cerebral artery just above the rhinal fissure. The animals were injected intravenously with the photosensitizing dye rose bengal, and the distal middle cerebral artery was irradiated with light from an argon laser-activated dye laser at three separate points to induce thrombotic occlusion. The ipsilateral common carotid artery was then permanently occluded, and the contralateral common carotid artery was occluded for 60 minutes. Three days later, the brains were perfusion-fixed and prepared for histopathologic examination, and infarct volume was determined by quantitative planimetry. RESULTS: In Sprague-Dawley rats, a large consistent temporoparietal cortical infarct was observed; mean +/- SD infarct volume was 130.5 +/- 40.0 mm3 (coefficient of variation, 30.7%) and a relatively small adjacent zone of selective neuronal necrosis ("incomplete infarction"), amounting to only 9.1% of the total injury volume, was also seen. By contrast, Wistar rats had smaller and more variable cortical infarcts (volume, 48.4 +/- 26.9 mm3; coefficient of variation, 55.6%) but displayed a much more substantial zone of incomplete cortical infarction (volume, 20.8 +/- 10.1 mm3; 30.1% of the total injury volume). In neither strain was infarct size related to alterations of blood pressure. In both strains, infarcts were limited to the cortex, typically involving the parietal cortex, somatosensory cortex, and forelimb region. Three rats exhibited infarcts in the contralateral hemisphere. CONCLUSIONS: This model has the advantages of necessitating only minimal surgery, allowing the dura to remain intact, and avoiding mechanical trauma to the brain surface. In Sprague-Dawley rats, the resulting large cortical infarct exhibited relatively small interanimal variation, making the model suitable, for example, for replicate studies of pharmacotherapy. In Wistar rats, the large zone of incomplete infarction, a unique feature heretofore undescribed in rodent models of permanent focal ischemia, lends the model to the study of the pathomechanisms underlying graded cortical ischemic injury.

Animals↗
PubMed1999

Supplement to the Carcinogenic Potency Database (CPDB): results of animal bioassays published in the general literature in 1993 to 1994 and by the National Toxicology Program in 1995 to 1996.

The Carcinogenic Potency Database (CPDB) is a systematic and unifying analysis of results of chronic, long-term cancer tests. This paper presents a supplemental plot of the CPDB, including 513 experiments on 157 test compounds published in the general literature in 1993 and 1994 and in Technical Reports of the National Toxicology Program in 1995 and 1996. The plot standardizes the experimental results (whether positive or negative for carcinogenicity), including qualitative data on strain, sex, route of compound administration, target organ, histopathology, and author's opinion and reference to the published paper, as well as quantitative data on carcinogenic potency, statistical significance, tumor incidence, dose-response curve shape, length of experiment, duration of dosing, and dose rate. A numerical description of carcinogenic potency, the TD(subscript)50(/subscript), is estimated for each set of tumor incidence data reported. When added to the data published earlier, the CPDB now includes results of 5,620 experiments on 1,372 chemicals that have been reported in 1,250 published papers and 414 National Cancer Institute/National Toxicology Program Technical Reports. The plot presented here includes detailed analyses of 25 chemicals tested in monkeys for up to 32 years by the National Cancer Institute. Half the rodent carcinogens that were tested in monkeys were not carcinogenic, despite usually strong evidence of carcinogenicity in rodents and/or humans. Our analysis of possible explanatory factors indicates that this result is due in part to the fact that the monkey studies lacked power to detect an effect compared to standard rodent bioassays. Factors that contributed to the lack of power are the small number of animals on test; a stop-exposure protocol for model rodent carcinogens; in a few cases, toxic doses that resulted in stoppage of dosing or termination of the experiment; and in a few cases, low doses administered to monkeys or early termination of the experiment even though the doses were not toxic. Among chemicals carcinogenic in both monkeys and rodents, there is some support for target site concordance, but it is primarily restricted to liver tumors. Potency values are highly correlated between rodents and monkeys. The plot in this paper can be used in conjunction with the earlier results published in the CRC Handbook of Carcinogenic Potency and Genotoxicity Databases [Gold LS, Zeiger E, eds. Boca Raton FL:CRC Press, 1997] and with our web site (http://potency.berkeley.edu), which includes a guide to the plot of the database, a complete description of the numerical index of carcinogenic potency (TD50), and a discussion of the sources of data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. Two summary tables permit easy access to the literature of animal cancer tests by target organ and by chemical. For readers using the CPDB extensively, a combined plot on diskette or other format is available from the first author. It includes all results published earlier and in this paper, ordered alphabetically by chemical. A SAS database is also available.

Animals↗
PubMedDate not supplied

The role of obesity, hypertension and diet in diabetes and its complications in the Spontaneous Hypertensive/NIH-corpulent rat.

The Spontaneous Hypertensive/NIH-corpulent rat is a recently developed genetic model of obesity and diabetes. The strain exhibits both metabolic and histopathological characteristics associated with non-insulin dependent diabetes mellitus in humans. This rodent model is unique in that glucose intolerance is expressed in both sexes and in both phenotypes.

Animals↗
PubMed1993

Use of genetically distinct mouse populations to explore ethanol reinforcement.

Alcohol-induced locomotor stimulation in mice may provide an animal model of human euphoric responses to moderate alcohol (ethanol) doses. If a common mechanism mediates sensitivity to both drug reward (reinforcement) and drug stimulation, rodent models of drug stimulation would provide powerful tools for investigating drug reinforcement. In addition, stimulant sensitivity might provide a simple marker for susceptibility to ethanol reward, and perhaps addiction (e.g., Newlin and Thomson, 1991). This short report describes the use of three genetic mouse models, (1) FAST and SLOW selectively bred lines, (2) BXD Recombinant Inbred Strains, and (3) a panel of inbred strains of diverse genetic origin, to explore mechanisms mediating ethanol stimulation and reinforcement.

Animals↗
PubMed2004

A mouse model for studying intrahepatic islet transplantation.

Intrahepatic human islet transplantation has raised hopes for a cure for diabetes mellitus, especially in patients with type 1 diabetes; however, the need for a substantial amount of islets and, in many instances, repeated transplantations demonstrates underlying problems with this procedure, such as failure of angiogenesis and immunologic rejection. Studies using rodent models may be helpful in improving the success of islet transplantation. However, most of the studies using rodents for islet transplantation have been under the kidney capsule rather than the liver. Using islets from transgenic mice expressing green fluorescent protein under the control of mouse insulin I promoter, the authors have developed a method with which to visualize histologic and pathologic changes in intraportally transplanted islets and surrounding hepatic tissue using reflected light confocal imaging. Initial events 24 hr after islet transplantation in the liver include beta-cell loss and hepatic ischemic injuries.

Animals↗
PubMed1994

Action of pentamidine-bound nanoparticles against Leishmania on an in vivo model.

The efficiency of antileishmanial agents may be enhanced by improving their bioavailability with a colloidal drug carrier. We have investigated the action of free pentamidine, compared with pentamidine bound to polymethacrylate nanoparticles, in a rodent model. BALB/c mice were infected, via the tail vein, with 4 x 10(7) L. major (MON 74) promastigotes. Twelve days after infection, seven groups of mice were treated respectively with methylglucamine antimoniate (Glucantime) 5.56 mg/kg i.p. x 5 d., pentamidine bound nanoparticles (100 microM), unloaded polymethacrylate nanoparticles, unloaded nanoparticles associated with free pentamidine (100 microM) 0.1 ml i.v. x 3 d and free pentamidine isethionate (2.28 mg/kg and 0.17 mg/kg i.v. x 3 d.). Twenty-one days post infection, the mice were sacrificed and the Leishmania load in the liver calculated from the number of amastigotes/500 liver cells and total liver weight in treated and untreated mice. Results demonstrated a 77% amastigote reduction in the group treated with targeted pentamidine relative to the control group. The ratio free pentamidine/bound-pentamidine was approx. 12.

Animals↗
PubMed1999

Esophagogastric anastomotic wound healing in rats.

Esophagectomy with esophagogastric anastomosis is commonly complicated by anastomotic dehiscence. Although this is a major problem in clinical esophageal surgery, laboratory investigation of esophagogastric anastomotic wound healing has been hampered by the lack of a practical rodent model. Problems with aspiration pneumonia and anastomotic strictures hindered our previous studies in the rat. Other researchers have turned to large animal experiments, or used various upper gastrointestinal pseudoanastomotic techniques in rodents. None of these approaches has proved satisfactory. We developed a technique of side-to-side esophagogastric anastomosis in the rat, and then studied normal esophagogastric anastomotic healing in this model. Anastomoses were performed in 24 rats. Anastomotic breaking strength and hydroxyproline concentration were measured 1 and 2 weeks after surgery. Anastomotic breaking strength was 3.78 +/- 1.18 N at 1 week and 4.83 +/- 0.91 N after 2 weeks (p < 0.03). Anastomotic tissue hydroxyproline concentration was 370.6 +/- 31.2 nmol/mg at 1 week and 462.1 +/- 69.7 nmol/mg after 2 weeks (p < 0.001). Many of the problems encountered in esophagogastric anastomotic studies in the rat have been overcome using this new model.

Anastomosis, Surgical↗
PubMed2005

Animal models of leptomeningeal cancer.

Animal models are a critical tool for our understanding of pathogenic mechanisms and the development of therapeutic strategies. Since the 1970's, numerous syngeneic and allogeneic rodent models of leptomeningeal cancer have been developed; in this chapter, we present representative models and discuss their clinical and translational implications.

Animals↗
PubMed2003

Transgenic tumor models for carcinogen identification: the heterozygous Trp53-deficient and RasH2 mouse lines.

Genetically altered mouse models (GAMM) for human cancers have been critical to the investigation and characterization of oncogene and tumor suppressor gene expression and function and the associated cancer phenotype. Similarly, several of the mouse models with defined genetic alterations have shown promise for identification of potential human carcinogens and investigation of mechanisms of carcinogen-gene interactions and tumorigenesis. In particular, both the B6.129N5-Trp53 mouse, heterozygous for a p53 null allele, and the CB6F1-RasH2 mouse, hemizygous for the human H-ras transgene, have been extensively investigated. Using 26-week exposure protocols at or approaching the maximum tolerated dose, the summary results to date indicate the potential for GAMM to identify and, possibly, classify chemicals of potential risk to humans using short-term carcinogenicity experiments. This IWGT session focused on: (1) the development of recommendations for genetic/molecular characterization required in animals, tissues, and tumors before and after treatment for identification of presumptive human carcinogens based on the current state of knowledge, (2) identification of data gaps in our current state of knowledge, and (3) development of recommendations for research strategies for further development of our knowledge base of these particular models. By optimization of protocols and identification of significant outcomes and responses to chemical exposure in appropriate short-term mechanism-based genetically altered rodent models, strategies for prevention and intervention may be developed and employed to the benefit of public health.

Animals↗
PubMed2004

Predictive values of traditional animal bioassay studies for human perinatal carcinogenesis risk determination.

The many physiological, biochemical, and structure differences between rodents and humans, especially with regard to gestation and fetal development, invite questions as to the utility of rodent models for the prediction of risk of perinatal carcinogenesis in humans and for extrapolation of mechanistic studies. Here, the relevance of basic generalities, derived from rodent perinatal studies, to human contexts is considered. The cross-species usefulness of these generalities was upheld by the example of carcinogen activation and detoxification as determining factors. These have been established in rodent studies and recently indicted in humans by investigations of genetic polymorphisms in cytochromes P450, N-acetyltransferase, myeloperoxidase, quinone reductase, and glutathione S-transferase. Also, published data have been analyzed comparatively for diethylstilbestrol and irradiation, the two known human transplacental carcinogenic agents. At similar doses to those experienced by humans, both diethylstilbestrol and X- and gamma-irradiation in rodents and dogs yielded increased tumors at rates similar to those for humans. In rodents, there was a clearly negative relationship between total diethylstilbestrol dose and tumors per dose unit, and a similar pattern was suggested for radiation. Diethylstilbestrol had transgenerational effects that did not diminish over three generations. Overall, this analysis of the published literature indicates that there are basic qualitative and quantitative similarities in the responsiveness of human and rodent fetuses to carcinogens, and that dose effects may be complex and in need of further investigation.

Adult↗
PubMed2006

Absorption of the nerve agent VX (O-ethyl-S-[2(di-isopropylamino)ethyl] methyl phosphonothioate) through pig, human and guinea pig skin in vitro.

The physico-chemical properties of VX make the skin the most likely route of absorption into the human body. The development of effective medical countermeasures against such percutaneous threat agents relies on the use of appropriate animal models, as the inherent toxicity of nerve agents precludes the use of human volunteers. Previous studies have characterised the mechanism of nerve agent toxicity in rodent models, however, it is generally accepted that one of the most appropriate animal models for human skin absorption is the domestic pig. The purpose of the present study was to measure and compare the skin absorption kinetics of VX in vitro using pig, human and guinea pig skin to highlight any potential species differences in skin permeability. When undiluted VX was applied directly to the skin, the permeability of guinea pig skin was approximately 7-fold greater than human skin. There was no significant difference in the permeability of pig and human skin. When VX diluted with isopropyl alcohol was applied to the skin, the permeability of guinea pig skin was approximately 4-fold greater than human skin. There was no significant difference in the permeability of pig and human skin. From this data it may be inferred that dermatomed, abdominal pig skin is an appropriate model for the human skin absorption of VX.

Adult↗
PubMed1998

Chronic recording of the vestibulo-ocular reflex in the restrained rat using a permanently implanted scleral search coil.

A technique is described which allows accurate long-term monitoring of eye movements in the rat using permanently implanted scleral search coils. Search coils permanently sutured around the sclera yield vestibulo-ocular reflex (VOR) gain and phase values which are comparable to those reported previously in the literature using acutely implanted coils or electrooculographic electrodes. Considerations related to strain, sex and surgical procedures which permit measurement of responses in the chronically restrained rat are described. VOR gain and phase show a time course to their recovery following the implant surgery, with asymptotic performance typically attained approximately 10 days post-surgically. This technique, with the ability to monitor eye movements over weeks to months, appears ideal for development of rodent models of reflex adaptation which require observation of reflex behavior over extended periods of time. Development of a chronic procedure for monitoring eye movement in rodents is especially important given their initial response to restraint (extensive struggling). Finally, adaptation of this technique to smaller species (e.g., mouse) appears technically feasible which should permit the application of transgenic and knockout techniques to the determination of various vestibular reflex functions requiring long-term monitoring.

Animals↗
PubMed1998

Camptothecin-20-PEG ester transport forms: the effect of spacer groups on antitumor activity.

An improved synthesis of the hindered PEG-camptothecin diester transport form has been achieved using the Mukaiyama reagent. We have also assessed the effect of changing the electronic configuration of the (d-position of PEG-camptothecin transport forms on the rates of hydrolysis of the pro-moiety, and attempted to correlate these differences to efficacy in two animal models. In addition to the simple substitution of N for O, other synthetic modifications of these atoms were accomplished by employing heterobifunctional linker groups. The half lives by disappearance (rates of hydrolysis) of the transport forms in buffer and rat plasma were determined. It was established that anchimeric assistance to hydrolytic breakdown of the pro-moiety occurs in a predictable manner for some of these compounds. Results for the new derivatives in a P388 murine leukemic model and HT-29 human colorectal xenograft study are also presented. The use of a glycine linker group was found to provide similar efficacy in rodent models to that of simple camptothecin 20-PEG ester, and displayed enhanced pharmacokinetics.

Animals↗
PubMed2006

Endocannabinoids potently protect the newborn brain against AMPA-kainate receptor-mediated excitotoxic damage.

Brain lesions induced in newborn mice or rats by the glutamatergic agonists ibotenate (acting on NMDA and metabotropic receptors) or S-bromowillardiine (acting on AMPA-kainate receptors) mimic some aspects of white matter cysts and transcortical necrosis observed in human perinatal brain damage associated with cerebral palsy. Exogenous and endogenous cannabinoids have received increasing attention as potential neuroprotective agents in a number of neurodegenerative disorders of the adult. One recent study showed neuroprotection by the cannabinoid agonist WIN-55212 in a newborn rat model of acute severe asphyxia. The present study was designed to assess the neuroprotective effects of the endogenous cannabinoid anandamide using a well-defined rodent model of neonatal excitotoxic brain lesions. In this model, anandamide provided dose-dependent and long-lasting protection of developing white matter and cortical plate reducing the size of lesions induced by S-bromowillardiine. Anandamide had only marginal neuroprotective effect against ibotenate-induced cortical grey matter lesions. Anandamide-induced neuroprotection against AMPA-kainate receptor-mediated brain lesions were blocked by a CB1 antagonist but not by a CB2 antagonist. Furthermore, anandamide effects were mimicked by a CB1 agonist but not by a CB2 agonist. Real-time PCR confirmed the expression of CB1 receptors, but not CB2 receptors, in the untreated newborn neocortex. Finally, neuroprotective effects of anandamide in white matter involved increased survival of preoligodendrocytes and better preservation of myelination. The present study provides experimental support for the role of endocannabinoids as a candidate therapy for excitotoxic perinatal brain lesions.

Animals↗