Osteoarthritis (OA) was induced in the rat stifle joint by partial medial meniscectomy (PMM) and transection of the cranial cruciate ligament (CCL). At 10 weeks after destabilization, joint morphologic and pathologic changes were observed, scored, and compared. The intact rat stifle joint was observed in a mid-saggital plane. Articular cartilage of the distal portion of the femur and proximal portion of the tibia had thicker and thinner sites, and the thicker sites were located caudally on the distal portion of the femur and centrally on the proximal portion of the tibia. The two separate triangular portions of the medial meniscus observed in the mid-saggital plane contained a center of ossification in the cranial portion and fibrocartilage in the caudal portion. The synovium was one to three cells thick, and contained rare inflammatory cells. Although lesions were more severe in stifles after PMM, both treatments produced OA lesions that closely simulated OA lesions of other species. Lesions consistent with idiopathic OA included chondrocytic clones with increased metachromasia around them, chondrocytic death, loss of metachromasia, fibrillation, fissuring, erosion of articular cartilage, osteophyte formation, and variable synovial inflammation. The results indicate that PMM and CCL transection in the rat are useful in vivo models for study of the etiopathogenesis of OA and therapeutic efficacy of anti-arthritic drugs and treatment concepts.

Effects of prescribed doses of ketamine five minutes after application and influences of transesophageal echocardiography (TEE) on left ventricular, systemic arterial, and baroreflex responses were investigated to test the hypothesis that ketamine and/or TEE probe insertion alter cardiovascular function. Seven rhesus monkeys were tested under each of four randomly selected experimental conditions: (1) intravenous bolus dose of ketamine (0.5 ml), (2) continuous infusion of ketamine (500 mg/kg/min), (3) continuous infusion of ketamine (500 mg/kg/min) with TEE, and (4) control (no ketamine or TEE). Monkeys were chronically instrumented with a high fidelity, dual-sensor micromanometer to measure left ventricular and aortic pressure and a transit-time ultrasound probe to measure aortic flow. These measures were used to calculate left ventricular function. A 4-element Windkessel lumped-parameter model was used to estimate total peripheral resistance and systemic arterial compliance. Baroreflex response was calculated as the change in R-R interval divided by the change in mean aortic pressure measured during administration of graded concentrations of nitroprusside. The results indicated that five minutes after ketamine application heart rate and left ventricular diastolic compliance decreased while TEE increased aortic systolic and diastolic pressure. We conclude that ketamine may be administered as either a bolus or continuous infusion without affecting cardiovascular function 5 minutes after application while the insertion of a TEE probe will increase aortic pressure. The results for both ketamine and TEE illustrate the classic “Hawthorne Effect,” where the observed values are partly a function of the measurement process. Measures of aortic pressure, heart rate, and left ventricular diastolic pressure should be viewed as relative, as opposed to absolute, when organisms are sedated with ketamine or instrumented with a TEE probe.

The thyroparathyroidectomized (TPTx) rat has been extensively used to study parathyroid hormone (PTH)-mediated bone resorption by measuring systemic Ca²⁺ concentrations. Animals have been traditionally used acutely; that is, they are often infused immediately after surgery and are sacrificed after a single use. To perform multiple experiments using a single group of animals we developed a system of long-term implanted intravenous/arterial catheters. Using calcitonin (CT) as a positive control, we successfully completed 12 separate controlled subexperiments documenting significant reductions in PTH-induced hypercalcemia in rats of the CT group. We then successfully completed two separate TPTx subexperiments, using a 3 × 3 Latin square experimental design. In both subexperiments, CT significantly inhibited the increase of blood Ca²⁺ concentration resulting from continuous PTH infusion. Our results indicate that, by combining the long-term use of catheters with the Latin square design, we can successfully reduce the number of animals used, increase the number of compounds screened, and improve the quality of the data. Although results of this study confirmed the acceptability of multiple infusions in anti-resorptive studies, investigations into the applicability of this set up to other areas of study requiring infusions and frequent blood sample collections seem appropriate.

Transcutaneous blood gas (TCBG) analysis is a noninvasive alternative method of estimation of blood gas tensions. The objective of the study reported here was to validate this method against standard blood gas (STBG) analysis in adult and juvenile Sprague-Dawley rats. We sought to establish the optimal TCBG probe site and temperature, to establish probe temperatures that would not cause thermal burns, to evaluate correlations between blood gas values (P_aCO₂ and P_aO₂ ) determined by use of TCBG and STBG, and to evaluate the sensitivity of the TCBG unit to changes in arterial blood gas partial pressures. Our results indicated that: in general, the xyphoid area was the optimal site for probe placement, with 44.5°C being the optimal probe temperature for the highest correlation, but thermal burns may be a problem; probe temperatures of 42.5°C (adults) and 42.0°C (juveniles) do not cause thermal burns when left in place for three hours; probe temperatures of 44°C (adults) and 42°C (juveniles) resulted in moderate correlation between P_a CO_{2 and Ptc} CO₂ ; and the TCBG unit adequately responded to changes in arterial blood gas partial pressures. Neither P_tcCO₂ or P_tcO₂ reflect actual values of P_aCO₂ or P_aO₂, respectively. We concluded that TCBG analysis may be used as an indicator of change in P_a CO₂ with sufficient animal numbers under tightly controlled conditions, but not as an indicator of change in P_aO₂ in adult and juvenile rats.

Background and Purpose: The least shrew is an established animal model for reproductive and pharmacologic research. Biologic reference data are needed to assess animal health status and provide a rationale for use of novel statistical programs to evaluate the effects of orally administered substances in toxicologic and pharmacologic studies. Methods: Organ weights, blood biochemical and hematologic values, and food and water consumption data were collected from 50-day-old shrews after two weeks' consumption of a standard feline diet. Results: In general, data correlated well with values reported for other mammalian species. Plasma phosphorus concentration was high. There was a significant difference in food and water consumption per gram of body weight between shrews at lower and upper (± 1 SD) weight ranges for the study. The 3.2-g animals consumed 27% more food per gram of body weight than did the 5.0-g animals. Conclusions: The high phosphorus concentration was attributed to hemolysis resulting from the axillary cut method of blood sample collection. The small size of the shrew allowed demonstration of the Kleiber effect within a ± 1 SD weight range in a single species. The phenomenon necessitates the use of statistical methods other than the typical tests establishing the significance of the differences between the means of groups for oral toxicologic and pharmacologic studies.

We investigated whether infection of beige/scid mice with Mycobacterium avium subspecies paratuberculosis can induce intestinal pathophysiologic changes. Six-week-old beige/scid mice were inoculated intraperitoneally with M. paratuberculosis, then were killed 32 weeks after inoculation when the small intestine was evaluated for physiologic and morphologic abnormalities. All infected mice developed clinical disease. The lamina propria of the intestine from infected mice was mildly infiltrated with mononuclear cells containing acid-fast bacteria, and had significantly increased villus width. In vitro physiologic studies in Ussing chambers indicated that M. paratuberculosis infection caused significant abnormalities in intestinal transport parameters. Baseline short circuit current and potential difference were abnormally high in tissues from infected, compared with control mice, indicative of increased ion secretion. Baseline conductance was significantly decreased in infected mice, suggesting that intestinal tissue from infected mice was less permeable to ions. The change in short circuit current following transmural electrical and glucose stimulation was significantly reduced in intestines from infected mice, suggesting that inflamed intestine had neural and/or epithelial cell damage. We conclude that infection of beige/scid mice with M. paratuberculosis triggers significant intestinal pathophysiologic changes consistent with chronic inflammation. These functional abnormalities may contribute to the pathogenesis of the wasting syndrome seen in bovids with paratuberculosis. This animal model provides evidence that T cell-independent mechanisms are sufficient to cause mucosal pathophysiologic changes and inflammation in response to a specific pathogen, and may be of relevance to inflammatory bowel disease in humans.

Purpose: Echocardiography played an important role in the screening and diagnosis of hypertrophic cardiomyopathy. In the study reported here, we attempted to evaluate the effects of birth season, breed, sex, and sire family on cardiac morphology determined in pigs by use of echocardiography. Methods: A total of 411 pigs (mean body weight and age of 105.7 ± 10.6 kg and 214.4 ± 25.5 days, respectively) with different genetic backgrounds (Landrace, Yorkshire, and their two-way crossbred) were studied. Cardiac morphologic measurements included thickness of left ventricle and interventricular septum at end-systolic and end-diastolic phases. Meanwhile, the statistical model included the following effects: birth season, breed, sex, interaction between breed and sex, sire family, body weight, and age. Results: Mean cardiac morphologic measurements were as follows: thickness of the interventricular septum at endsystolic and end-diastolic phases was 1.74 and 1.14 cm, respectively; and thickness of the left ventricular free wall at end-systolic and end-diastolic phases was 1.81 and 0.98 cm, respectively. Medium positive correlations existed among the cardiac morphologic measurements r = 0.31 to 0.53; P < 0.001). Pigs born in spring had significantly ( P < 0.05) lower cardiac thickness at the end systolic phase than did pigs born in other seasons, and Landrace pigs had higher cardiac morphologic measurements than did Yorkshire and two-way crossbred pigs. Additionally, thickness of interventricular septum at the end-diastolic phase in male pigs was significantly higher than that in female pigs (P < 0.05). Cardiac morphologic measurements for the sire family were significantly (P < 0.05) different, and contributed 77.2 to 87.9% of the total variation, suggesting that genetic variation in cardiac morphology might exist in pigs. Conclusions: Cardiac morphology of pigs might be influenced by genetic background. The effects of birth season, breed, sire family, and sex should be adjusted when using pigs as an animal model for comparative cardiovascular studies.

Mutant mice with abnormalities are potentially useful as models for studying human defects. Here we report a group of mice with abnormal behavioral patterns. A new spontaneous mutant mouse exhibited hyperactive behavior at about seven days of age, followed by tight circling behavior. Breeding studies suggest that this mutation is caused by a single gene defect inherited in an autosomal recessive manner. Consequently, this mutation is referred to as a circling (cir) mouse mutation with the gene symbol cir. Auditory test results identified clearly the hearing loss of the cir, compared with wild-type mice. Pathologic studies confirmed developmental defects in cochlea and spiral ganglions that were correlated to the abnormal behavior observed in the cir mice. Thus, cir mice may be useful as a model for studying inner ear abnormalities and deafness in humans.

The major histocompatibility complex (MHC) comprises related gene families, some of which are highly polymorphic, whose protein products mediate immune response. Rhesus macaques (Macaca mulatta) are a vital animal model for research in human diseases and are native to regions extending from Afghanistan in the west to the Eastern Plains of China and from Peking to the north, southward through islands of Southeast Asia. The distributions of MHC class-II Mamu DQA1 and Mamu DQB1 alleles in two groups of domestically bred rhesus macaques of Indian and Chinese origin and the Mamu DQA1 genotypes of a small number of Burmese rhesus macaques were compared. Major allelic differences were observed between the Indian and Chinese rhesus macaques, and gene diversity decreased from east to west. These and other intra-specific genetic differences among regional populations of rhesus macaques might influence the outcome of biomedical research in which they are used as subjects, and illustrate the importance of completely genetically characterizing subjects used as animal models in biomedical research.

A 27-year-old female rhesus macaque (Macaca mulatta) developed anisocoria. The left pupil was dilated and unresponsive to light. The macaque was euthanized because of unrelated reasons and the body was submitted for necropsy. On gross examination, a berry aneurysm of the right middle cerebral artery causing marked compression of the right optic tract was found. Arteriosclerotic changes were observed microscopically in the right middle cerebral and in the internal carotid arteries. The left iris was markedly degenerated, with atrophy of the constrictor muscle. Compression of the right optic tract may cause homonimus hemianopsia. A dilated and unresponsive left pupil indicated a lesion in the ipsilateral parasympathetic efferent pathway. In the absence of appreciable lesions of the left oculomotor nerve, the most likely cause of mydriasis was the iridic lesion. Intracranial aneurysms are common in humans (2 to 5%), but not in other species. Only about 10% of unruptured aneurysms are associated with neurologic deficits related to mechanical compression, such as visual deficits or anisocoria. Meticulous investigation of the ocular vascular and neural pathways led us to conclude that the anisocoria was unrelated to the aneurysm. To our knowledge, this report represents the first documented case of a naturally occurring intracranial aneurysm in nonhuman primates.