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A proteomic study on the tibial subchondral bone in guinea pigs with spontaneous osteoarthritis was performed to investigate the molecular alterations that occur in early osteoarthritis. A total of 132 healthy Hartley guinea pigs (aged 1 month; 66 female and 66 male) were randomly divided into 11 groups of six. Changes in articular cartilage and tibial subchondral bone were assessed using macroscopic examinations and micro-computed tomography. iTRAQ-integrated liquid chromatography-tandem mass spectrometry was used to identify differentially altered proteins in the tibial subchondral bone between 1- and 3-month-old guinea pigs, which were then validated using western blotting. A gradual progression of cartilage degeneration was observed in the knee joints of the subject animals from 5-11 months. With aging, the tibial subchondral trabecular bone acquired more plate-like and less anisotropic properties, with increased bone mineral density, bone volume, trabecular thickness and numbers. The proteomic study identified 138 and 113 proteins significantly differentially expressed between 3- and 1-month old guinea pigs in both the male and female animals, respectively. Western blotting confirmed the increased expression of osteoblast-associated protein S100 calcium-binding protein A8 (S100A8) and the deregulated expression of osteoclast-associated proteins coronin 1A (CORO1A) and T-cell immune regulator 1 (TCIRG1) in the 3-month old guinea pigs in comparison to the 1-month old guinea pigs. Spontaneous cartilage degeneration in the knee joints of male Hartley guinea pigs tended to be more serious compared with the females during the development of osteoarthritis. Together, the results suggest that osteoblast-associated protein S100A8 and osteoclast-associated proteins CORO1A and TCIRG1 are potentially key regulators of early osteoarthritic development in tibial subchondral bone.

There is potential discrepancy between human and laboratory animal studies of osteoarthritis (OA), as radiographic assessment is the hallmark of the former and histopathology the standard for the latter. This suggests a need to evaluate OA in animal models in a manner similar to that utilized in people. Our study aimed to develop a whole joint grading scheme for microcomputed tomography (microCT) images in Hartley guinea pigs, a strain that recapitulates joint changes highlighted in human spontaneous OA.Knees from animals aged 2, 3, 5, 9, and 15 months were evaluated via whole joint microCT and standard histologic scoring. Quantitative microCT parameters, such as bone volume/total volume were also collected.Both whole joint microCT and histologic scores increased with advancing age and showed strong correlation (r = 0.89. p 0.0001). Histologic scores, which focus on cartilage changes, increased progressively with age. Whole joint microCT scores, which characterize bony changes, followed a stepwise pattern: scores increased between 3 and 5 months of age, stayed consistent between 5 and 9 months, and worsened again between 9 and 15 months.This work provides data that advocates the use of a whole joint microCT scoring system in guinea pig studies of OA, as it provides important information regarding bony changes that occur at a different rate than articular cartilage changes. This grading scheme, in conjunction with histology and quantitative microCT measurements, may enhance the translational value of this animal model as it pertains to human work.

Across the world, dozens of outbred Hartley guinea pig stocks are used for auditory experiments. The genetic makeup of these different stocks will differ due to differences in breeding protocols, history and genetic drift. In fact, outbred breeding protocols are not intended to produce genetically identical animals, neither across breeders, nor across time. For this reason, it is unclear how reproducible experimental results are likely to be using animals from different stocks. We evaluated the consistency of cochlear function using both clicks and tones in Hartley guinea pigs as a function of breeder (Kuiper and Charles River) and sex using archival Auditory Brain Stem Response (ABR) data and tissue from our own laboratory. Sound levels required to reach baseline threshold for click-induced ABRs were similar between male Charles River and male Kuiper guinea pig stocks. However, the median and average thresholds after exposure to high level noise were larger in the Kuiper population than in the Charles River population with corresponding threshold shifts higher in the Kuiper than in the Charles River animals. We evaluated the relationship between pure-tone thresholds and sex, age, breeder stock, left or right cochleas, weight and 5 test frequencies before and after noise exposure using a linear mixed statistical model. Across all frequencies, the effect of breeder on baseline threshold is statistically significant, with effect sizes most pronounced at the lower frequencies before exposure to noise. After noise exposure, the differences are minimal in the model, indicating that differences in threshold shift are chiefly due to differences in initial baseline hearing. However, a contingency calculation comparing response/no response at the highest speaker output at 32 kHz gave a statistically significant difference between the stocks: 28% of Kuiper cochleas responded to the highest output of the speaker as compared with 71.4% of Charles River cochleas, indicating that noise exposure induced a larger threshold shift in a greater proportion of Kuiper animals. Using our archival cochlear tissue from these studies, we confirmed the sex of each animal by PCR, then compared males and females of the Kuiper stock. Across all baseline frequencies, the effect of sex on threshold is statistically significant, with no noticeable difference after exposure. The effect sizes for baseline thresholds are most pronounced at lower frequencies. These data demonstrate that Hartley guinea pig stocks from different breeders are not uniform in their auditory characteristics, and that due to these differences, results and conclusions can differ among laboratories. Moreover, within a single stock, males and females can provide different data, confirming that male and female animals must be individually evaluated in any auditory protocol.

SummaryObjectiveTo assess the potential protective effects of three polyphenols oleuropein, rutin and curcumin, on joint ageing and osteoarthritis (OA) development.DesignSixty 4-week-old Dunkin–Hartley guinea pigs were randomized into four groups and received daily during 31 weeks either standard guinea pig diet (control group) or a standard guinea pig diet enriched with oleuropein (0.025%), rutin (0.5%) or rutin/curcumin (0.5%/0.25%) association. Biomarkers of OA (Coll2-1, Coll2-1NO2, Fib3-1, Fib3-2, ARGS), as well as inflammation prostaglandin E2 (PGE2) were quantified in the serum. Histological assessments of knee cartilage and synovial membrane were performed at week 4 (five young reference guinea pigs) and week 35.ResultsAt week 35, guinea pigs in the control group spontaneously developed significant cartilage lesions with mild synovial inflammation. The histological scores of cartilage lesions and synovitis were well correlated with the increased level of serum biomarkers. Histologically, all treatments significantly reduced the cartilage degradation score (P

Hartley guinea pigs are widely used animal models of disease, particularly in studies of osteoarthritis. The purpose of this study was to investigate lesions in the costal cartilage from 16 male, 5- to 6-month-old Hartley guinea pigs. Routine histological sections from the costal cartilage and costochondral junction (longitudinal and cross sections) and sternum (for evaluation of bone marrow) were examined. All 16 (100%) animals had histological lesions involving the costal cartilage that included matrix degeneration and mineralization, reduced cellularity, and evidence of chondrocyte necrosis. Of the 16, 4 (25%) of the lesions contained blood vessels and 3 (19%) contained central osseous metaplasia. The cartilage lesions were accompanied by degeneration (sometimes with regeneration and/or fibrosis) in adjacent skeletal muscle in 15 of the 16 (94%) animals. The lesions in the costal cartilage were interpreted as dystrophic mineralization of unknown cause and appear to be incidental findings, although they bear some resemblance to lesions occurring in Tietze’s disease in humans. The significance of the lesions in skeletal muscle is unclear. Histological lesions of cartilage matrix degeneration and mineralization in these sites have not, to our knowledge, been reported previously.

Objective.To investigate the expression of peroxisome proliferator-activated receptors (PPAR) α, β, and γ, and hematopoietic and lipocalin-type prostaglandin D synthase (H- and L-PGDS) over the course of osteoarthritis (OA) in the spontaneous Hartley guinea pig and the anterior cruciate ligament transection dog models.Methods.Guinea pigs were sacrificed at 2 (control group), 4, 8, and 12 months of age (n = 5 per group). Non-operated (control) and operated dogs were sacrificed at 4, 8, and 12 weeks postsurgery. Cartilage was evaluated histologically using the Osteoarthritis Research Society International (OARSI) guidelines. The expression of PPAR-α, β, γ, and H- and L-PGDS was evaluated by real-time PCR and immunohistochemistry. The nonparametric Spearman test was used for correlation analysis.Results.PPAR-α, β, and γ were detected in medial tibial plateau from control animals in both the spontaneous and surgical models. Levels of PPAR-α and β did not change over the course of OA, whereas PPAR-γ levels decreased during progression of disease. We also observed that the expression of H-PGDS remained unchanged, whereas L-PGDS increased over the course of OA. PPAR-γ levels correlated negatively, whereas L-PGDS levels correlated positively, with the histological score of OA.Conclusion.The level of PPAR-γ decreased, whereas level of L-PGDS increased during the progression of OA. These data suggest that reduced expression of PPAR-γ may contribute to the pathogenesis of OA, whereas enhanced expression of L-PGDS may be part of a reparative process.

Histological and molecular changes were examined to investigate the effects of long-term administration of glucosamine (GlcN) and chondroitin sulfate (CS) in a model of spontaneous osteoarthritis (OA) in Hartley guinea pigs. Three groups of female 3-week-old Hartley guinea pigs received GlcN, CS, and neither agent, respectively. Five animals in each group were sacrificed at 8, 12, and 18 months of age. At 8 months of age, Hartley guinea pigs had severe degeneration of knee joint cartilage, chondrocyte apoptosis, marked reduction of tissue total RNA, decreases of aggrecan and collagen type 2 mRNAs, and increases in MMP-3 and MMP-8 mRNAs. Long-term administration of GlcN and CS reduced cartilage degeneration at 8 months of age. The marked loss of total RNA and the increase in MMP-3 mRNA were also inhibited by GlcN and CS. Thus, long-term oral administration of GlcN or CS inhibits OA progression, maintains total RNA and down-regulates MMP-3 mRNA in a spontaneous OA model in Hartley guinea pigs.

Species independence of brain tissue binding was assessed with a large number of structurally diverse compounds using equilibrium dialysis with brain homogenates of seven species and strains (Wistar Han rat, Sprague-Dawley rat, CD-1 mouse, Hartley guinea pig, beagle dog, cynomolgus monkey, and human). The results showed that the fractions unbound of the seven species and strains were strongly correlated with correlation coefficients ranging from 0.93 to 0.99. The cross-species/strain correlations were not significantly different from the interassay correlation with the same species. The linear correlation between Wistar Han and other species had a slope close to 1 and an intercept near 0. Based on orthogonal statistical analysis, no correction is needed for extrapolation of fraction unbound from Wistar Han rat to the other species or strains. Hence, brain tissue binding of Wistar Han rat can be used to obtain binding of other species and strains in drug discovery.

Summary Objective A major barrier inhibiting the discovery of structural modifying agents for osteoarthritis (OA) is an incomplete understanding of early disease events. Herein, we investigated the time course of collagen II cleavage and fibril disruption in the well-validated Hartley guinea pig model of spontaneous OA of the knee. Methods Knee joints of 46 male Hartley guinea pigs were analyzed at 3 weeks, 2, 4, 7, 10, 12, and 18 months of age for histological severity of OA, cartilage collagen fibril disruption by semi-quantitative polarized light microscopy, and expression of type II collagen degradation biomarkers, 9A4 and Coll2-1, by immunohistochemistry. In addition, serum biomarkers specific for collagen II degradation, CTX-II, C2C, and Coll2-1 were quantified. Results Collagen fibril disruption and expression of the collagenase-generated cleavage neoepitope, 9A4, were observed as early as 2 months of age, despite the appearance of histological OA at 4 months of age. Only serum Coll2-1 increased coincident with the early disruption of the collagen fibril between 3 weeks and 7 months, in contrast to serum C2C, which did not change significantly or correlate with histological severity. Inversely, CTX-II declined dramatically from 3 weeks to 4 months and remaining low thereafter, coincident with growth plate turnover. Conclusions Collagenase cleavage and disruption of the type II collagen network are early OA disease events in this model, preceding histological evidence of proteoglycan loss. The markedly different serum profiles of collagen II-related biomarkers during the early stages of disease development suggest compartmental segregation and temporal regulation of collagen degrading enzymes.

The objective was to compare biomarkers of articular cartilage metabolism in synovial fluid from Hartley guinea pig knees, with and without anterior cruciate ligament transection (ACLT), to establish whether detectable differences in biomarker levels exist between primary and secondary osteoarthritis (OA). Synovial fluid lavages and knees were obtained from 3-month (control group) and 12-month (primary OA group) animals. Another group of animals (posttraumatic OA group) underwent unilateral ACLT at 3 months, and samples were obtained 9 months postsurgery. Synovial fluid concentrations of stromal cell-derived-factor (SDF-1), collagen fragments (C2C), proteoglycan (GAG), lubricin, matrix metalloproteinase-13 (MMP-13), and Interleukin-1 (IL-1beta) were evaluated. Cartilage damage was assessed via histology. The highest concentrations of C2C and SDF-1 in synovial fluid were found in the posttraumatic OA group, moderate concentrations were found in the primary OA group, and low concentrations in the control group. GAG release in synovial fluid was similar to C2C and SDF-1. The lubricin concentrations were significantly lower in ACLT joints than either the control or 12-month primary OA groups, but not between the control and primary OA groups. Higher levels of MMP-13 and IL-1beta were detected in the joints of the posttraumatic OA group as compared to the control or primary OA groups. Histology revealed greatest OA damage in the posttraumatic OA group, followed by moderate and minimal damage in primary OA and control groups, respectively. This study indicates that the biomarkers and progression of OA may differ in the Hartley guinea pig models with and without posttraumatic OA.

Purpose Altricial animals, such as rats and mice, are born with their eyes closed, compared to precocial animals, such as guinea pigs and humans, which have their eyes opened at birth. The purpose of this study was to investigate if the retina of guinea pigs (precocial animal) is subjected to a postnatal maturation process similar to that previously reported for rodents. Methods Photopic and scotopic electroretinograms (ERG) and retinal histology were obtained from albino guinea pigs aged P1 to P75. Results Photopic ERG responses reached maximal amplitudes at P5 (a-and b-waves), that is 5 days (b-wave) to 10 days (a-wave) earlier than scotopic responses. However, the postnatal gain in b-wave amplitude was significantly (P

Objective : To determine the material properties of articular cartilage in the Hartley guinea pig model of spontaneous osteoarthritis. Methods : Cartilage-bone samples from the medial femoral condyle and tibial plateau of 12 month-old guinea pig knees were subjected to osmotic loading. Site-matched swelling strains and fixed charge density values were used in a triphasic theoretical model for cartilage swelling to determine the modulus of the cartilage solid matrix. The degree of cartilage degeneration was assessed in adjacent tissue sections using a semi-quantitative histological grading scheme. Results : Decreased values for both moduli and surface zone fixed charge density were associated with increasing grades of cartilage degeneration. Decreases in moduli reflect damage to the collagen matrix, which give rise to greater swelling strains. Conclusion : Histological evidence of cartilage degeneration was associated with impaired cartilage mechanics in the aging Hartley guinea pig.

The i-wave, a post b-wave component of the human photopic electroretinogram (ERG), is claimed to originate at the level of the retinal ganglion cells (RGC) or more distally. We investigated whether this wave is a feature common to all species. Photopic ERGs were obtained from the following species: Beagle dog, European cat, New Zealand white rabbit, Göttingen minipig, Cynomolgus monkey, Sprague-Dawley and brown Norway rats, Hartley guinea pig, and CD1 and C57BL6 mice. Results were compared with those obtained from normal human subjects. Except for rats and mice, all species yielded a well-demarcated i-wave, easily identifiable and separated from the a-b-wave complex by approximately 20 ms. Our sample suggests that the i-wave is a feature common to the photopic ERG of most species including humans. In view of its suggested origin, the i-wave would offer a unique opportunity to test, with the flash ERG, the functional integrity of the retinal ganglion cells in animals where use of a pattern stimulus is not always easily obtained.

A young adult male Hartley guinea pig (Cavia porcellus) weighing 197 g (0.43 lb) was evaluated at the Comparative Pathology Branch, US Army medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Edgewood, Md, for a complete necropsy following sudden death; it had been observed alive approximately 1 hour earlier. The guinea pig, originally assigned to an active neurobehavior research protocol, was not used for that study because of low weight and poor growth.

Objective To analyze the in vivo compartmental expression of collagenases 1 and 3 (MMP-1 and MMP-13) in the Hartley guinea pig model of spontaneously occurring osteoarthritis (OA) for the purpose of elucidating their roles in the pathogenesis of OA. Methods Competitive reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry quantification of messenger RNA (mRNA) and protein levels in medial and lateral tibial cartilage obtained from the knee joints of 2-month-old (no OA) and 12-month-old (OA) guinea pigs. Results The patterns of mRNA expression of collagenases 1 and 3 varied with the age of the animal and the compartment of the knee. We also found focal areas of collagenase 1 and collagenase 3 proteins localized to the extracellular matrix of OA lesion sites, coincident with three-quarter/one-quarter collagen cleavage. Collagenase 3 protein was also abundant throughout the medial tibial cartilage of 2-month-old animals. Conclusion This represents the first description of bona fide collagenase 1 in a rodent species. Recent evidence, however, based on analysis of mitochondrial DNA homologies, suggests that the guinea pig is not a member of the order Rodentia and may be more closely allied with lagomorphs. This taxonomic controversy leaves open to question the issue of the expression of collagenase 1 in other rodents, such as mice and rats. The presence of active collagenases 1 and 3 at OA lesion sites is consistent with an important role of these enzymes in the cartilage degradation of OA in guinea pigs. The expression of collagenase 3 in medial tibial cartilage from 2-month-old guinea pigs may signify a role of this enzyme in cartilage remodeling with growth and development, or it may represent an early molecular manifestation of OA.

Bromobenzene is metabolized by the Hartley guinea pig to two different bromothiocatechols, 4-bromo-2-hydroxythiophenol and 5-bromo-2-hydroxythiophenol. Both the thiol and phenol functional groups of thiocatechol undergo biological methylation. Methylation at the thiol group leads to the formation of (methylthio)bromophenol (S-methylated bromothiocatechol), while methylation of the phenol group leads to methoxybromothiophenol (O-methylated bromothiocatechol). This resulted in the urinary excretion of four O- and S-methylated bromothiocatechols. Bromothiocatechols could be formed by dehydrogenation of their corresponding bromodihydrobenzene thiolols. Both the 3-S- and 4-S-bromodihydrobenzene thiolols, as S-methylated products, were found as urinary metabolites of bromobenzene in the Hartley guinea pig. All four O- and S-methylated bromothiocatechols and two S-methylated bromodihydrobenzene thiolols were also found as urinary metabolites of bromobenzene in the golden Syrian hamster.

Objective To develop an animal model for cytomegalovirus (CMV)–induced sensorineural hearing loss. Design Guinea pig model. Setting University of Utah otolaryngology research labs. Participants Thirty-one Hartley guinea pig pups were divided into 4 groups. Group 1 pups were delivered from pregnant dams inoculated with 1 × 10 5 plaque-forming units (PFU) of guinea pig CMV (gpCMV). Group 2 and group 3 pups were delivered from pregnant dams inoculated with higher doses of 2 and 4 × 10 5 PFU of gpCMV, respectively. Group 4 pups, the control group, were delivered from uninoculated dams. Main Outcome Measures All groups underwent weekly auditory brainstem response studies. Six weeks after delivery, the brain, cochlea, salivary glands, lungs, liver, and kidneys were harvested. All tissue except the cochlea was analyzed for histologic evidence of the virus. All tissue underwent polymerase chain reaction (PCR) to detect gpCMV. Results Seven of the 19 (37%) inoculated pups developed a 30-dB hearing loss; none of the animals in the control group had a worse click threshold than 20 dB. Group 1 pups demonstrated statistically significant asymmetric hearing loss. All 3 inoculated groups showed evidence of progressive hearing loss over time. The control group did not demonstrate evidence of progressive threshold worsening. The PCR testing detected gpCMV in the cochleas of group 2 and group 3 animals. Conclusions We have successfully demonstrated elevated auditory brainstem response click thresholds with characteristics of progressive and asymmetric loss that have been reported in clinical reports of congenital CMV infection. We also detected gpCMV via PCR testing in the cochleas of inoculated pups.

We have been investigating the suppression of experimental autoimmune encephalomyelitis (EAE) by oral tolerization to autoantigens. In the present study the tolerizing effect of orally administered myelin basic protein (MBP) from different species was examined in the Lewis rat, Hartley guinea pig, and SJL/J mouse model of EAE. Animals were fed guinea pig, rat, bovine, human or mouse-MBP and then immunized with the homologous species of MBP or myelin: Lewis rats were immunized with rat MBP, Hartley guinea pigs with guinea pig-MBP, and SJL/J mice with mouse myelin. Clinical expression of EAE and delayed-type hypersensitivity (DTH) responses to MBP were assessed. In each species, suppression of disease and DTH responses were most pronounced by tolerization with the homologous species of MBP. In addition, cross-species tolerization was observed in each species and in general was less suppressive than homologous MBP although in some instances MBP from a heterologous species was as effective as tolerization with the homologous species. We also studied guinea pig-MBP induced EAE in the Lewis rat because it is a widely studied model of EAE and found that oral tolerization with guinea pig MBP was as suppressive as rat MBP. Of note is that oral tolerization with mouse MBP suppressed myelin-induced EAE in the SJL mouse in which autoimmunity to proteolipid protein appears to play a primary role, suggesting that antigen-driven bystander suppression following oral tolerization with autoantigens (Miller et al., 1991b) may be an important contributing mechanism for suppression of EAE following oral tolerization with MBP in this model.(ABSTRACT TRUNCATED AT 250 WORDS)

In mature animals, the acute toxic potency of TCDD exhibits up to a 5000-fold interspecies variability in the Hartley guinea pig, Sprague-Dawley rat, and Golden Syrian hamster. The embryotoxic and teratogenic potential of TCDD was evaluated in these species to assess whether there is a similar interspecies variability in the developmental toxicity of TCDD. TCDD was a potent developmental toxicant in all three species. Teratogenic activity, consisting of hydronephrosis, was only observed in the hamster. The results indicate that although there are species and tissue specific responses associated with the developmental toxicity and teratogenicity of TCDD, the toxic potency of TCDD is similar (within 10-fold) during prenatal development in these species.

Summary Objective The Hartley guinea pig develops articular cartilage degeneration similar to that seen in idiopathic human osteoarthritis (OA). We investigated whether the application of pulsed low-intensity ultrasound (PLIUS) to the Hartley guinea pig joint would prevent or attenuate the progression of this degenerative process. Methods Treatment of male Hartley guinea pigs was initiated at the onset of degeneration (8 weeks of age) to assess the ability of PLIUS to prevent OA, or at a later age (12 months) to assess the degree to which PLIUS acted to attenuate the progression of established disease. PLIUS (30mW/cm 2 ) was applied to stifle joints for 20min/day over periods ranging from 3 to 10 months, with contralateral limbs serving as controls. Joint cartilage histology was graded according to a modified Mankin scale to evaluate treatment effect. Immunohistochemical staining for interleukin-1 receptor antagonist (IL-1ra), matrix metalloproteinase (MMP)-3, MMP-13, and transforming growth factor (TGF)-β1 was performed on the cartilage to evaluate patterns of expression of these proteins. Results PLIUS did not fully prevent cartilage degeneration in the prevention groups, but diminished the severity of the disease, with the treated joints showing markedly decreased surface irregularities and a much smaller degree of loss of matrix staining as compared to controls. PLIUS also attenuated disease progression in the groups with established disease, although to a somewhat lesser extent as compared to the prevention groups. Immunohistochemical staining demonstrated a markedly decreased degree of TGF-β1 production in the PLIUS-treated joints. This indicates less active endogenous repair, consistent with the marked reduction in cartilage degradation. Conclusions PLIUS exhibits the ability to attenuate the progression of cartilage degeneration in an animal model of idiopathic human OA. The effect was greater in the treatment of early, rather than established, degeneration.

Objective To evaluate the relationships among cartilage and subchondral bone before and after the onset of cartilage degeneration in the Hartley guinea pig model of spontaneous osteoarthritis (OA) as compared with those in Weiser-Maple guinea pigs, which do not develop OA. Methods Mice from each strain were used at ages 2, 3, 5, and 8 months (n = 7 at each time point). The region observed was the medial tibial plateau. Cartilage degeneration was evaluated histologically. Subchondral bone structure was evaluated based on subchondral bone plate thickness and subchondral cancellous bone trabecular parameters calculated from the microfocal computed tomography 3-dimensional reconstruction image. The bone mineral density (BMD) of the subchondral cancellous bone as well as levels of urinary N-telopeptide of type I collagen (NTX) and serum osteocalcin (OC) were measured. Results In Hartley guinea pigs, the number of chondrocytes in the surface layer started to decrease at 3 months. At 8 months, fibrillation expanded to the radial zone. In Weiser-Maple guinea pigs, no cartilage degeneration was noted even at 8 months. Subchondral bone plate thickness was significantly lower in Hartley guinea pigs than in Weiser-Maple guinea pigs at 2 months. The subchondral bone had a rod-like and convex structure at 2 months in Hartley guinea pigs. BMD was significantly lower in Hartley guinea pigs than in Weiser-Maple guinea pigs at 2 months. The serum OC level was significantly higher in Hartley guinea pigs than in Weiser-Maple guinea pigs at 2 months and 3 months, whereas the urinary NTX level was significantly lower in Hartley guinea pigs at 3 months. Conclusion Subchondral bone is fragile, and bone formation may be promoted in subchondral bone before the onset of cartilage degeneration in Hartley guinea pigs. Subchondral bone may be involved in the development of OA.

Summary Objective To evaluate chosen serum cytokines and their association with osteoarthritis (OA) in the guinea pig. Methods The levels of 18 cytokines were measured in Hartley guinea pig serum at time points ranging from 3 weeks to 18 months of age. These levels were then tested for any correlation with total histology, and a comprehensive evaluation of these statistics was conducted using data previously collected from OA-resistant Strain 13 guinea pigs. Results After all cytokines demonstrating a significant association with weight or age were excluded, IL-6 ( p =0.016) and G-CSF ( p =0.024) were found to correlate positively with total histological score. Models involving each of these cytokines paired independently with weight explained 43–44% of the variance in total histology. Conclusions Only the age and weight-independent associations of IL-6 and G-CSF with histological OA were significant under the conditions imposed by the Holm step-down adjustment for multiple comparisons. Though the observed changes of these cytokine levels may be due to a correlation with age, it is highly unlikely given the significant difference between Hartley and Strain 13 age-matched cohorts.

Acetaldehyde is a ubiquitous indoor and outdoor air pollutant. This vapor is a respiratory tract irritant and a rodent inhalation carcinogen. The current study was aimed at examining the upper respiratory tract (URT) deposition efficiency for this vapor at inspired concentrations of 1, 10, 100, or 1000 ppm in four rodent species: B6C3F1 mouse, Sprague-Dawley rat, Syrian hamster, and Hartley guinea pig. For measurement of vapor uptake, the URT was isolated in urethane-anesthetized animals via insertion of a polyethylene cannula in the trachea such that its tip lay at the larynx. Uptake was measured under constant velocity unidirectional inspiratory flow at flow rates of approximately 50, 100, 200, and 300% of the predicted minute ventilation of each species and also under pseudo-cyclic flow (sinusoidal flow at 100% of the predicted minute ventilation with a constant 7 ml/min bleed for analysis). In addition, aldehyde dehydrogenase (AldDH) activities were measured in whole nasal tissue homogenates from each species for comparative purposes. In all species a high-affinity (Km0.2 mM), low-capacity AldDH isozyme was observed. In the mouse, hamster, and rat, a low-affinity (Km10 mM), high-capacity isozyme was observed; this isozyme was not observed in nasal tissue homogenates of the guinea pig. In all species, URT deposition efficiency was strongly dependent on the inspired concentration, with uptake being two- to three-fold more efficient at inspired concentrations of 1 or 10 ppm than at 1000 ppm. For example, at flows approximating the twice-minute ventilation rate URT uptake efficiency averaged 43, 49, 28, and 43% in the mouse, hamster, rat, and guinea pig, respectively, at an inspired concentration of 10 ppm, compared to 27, 14, 16, and 6% at an inspired concentration of 1000 ppm. Species differences were observed in uptake efficiency. At an inspired concentration of 1000 ppm a two-factor analysis of variance followed by a Newman-Keuls test revealed that uptake was significantly higher in the mouse, rat, and hamster than in the guinea pig. In contrast, at 10 ppm uptake was significantly lower in the rat than in any other species. Thus, the rank order of these species on the basis of ability to scrub acetaldehyde from the airstream differed at high compared to low inspired concentrations. The documentation of greatly differing deposition efficiencies as well as differing relative dosimetric relationships among species at high compared to low exposure concentrations highlights the potential complexities of quantitative extrapolation of high-concentration rodent inhalation toxicity data.

The spontaneously diabetic adult male Abyssinian-Hartley guinea pig develops bladder hypertrophy and voiding dysfunction. In contrast to animals with chemically induced diabetes, this animal demonstrates changes in bladder function in the absence of diuresis. The diabetic guinea pigs void a total daily volume similar to that of control animals, but have a greater mean volume per void and a longer interval between voiding. Cystometry demonstrates that the diabetic guinea pig produces greater intraluminal bladder pressure, but maintains voiding pressure for a shorter interval. A significantly decreased contractile response of the diabetic bladder base may be responsible for the bladder hypertrophy and voiding dysfunction.

112 – Table 1. Comparison of biomarkers between groups Hand OA Non-Hand OA Controls Modified hand ACR criteria Ln HA 4.17 ±0.84 3.47±0.94** 3.08±1.01** Ln PIIANP 6.94±1.10 7.14±0.67++ Age, years (n) 68.0±11.7 (38) 53.7±14.6** (240) 47.2±13.6** (41)

Regional deposition patterns determine the dose of inhaled gaseous toxicant received by various areas of the respiratory tract. To study potential species differences in upper respiratory tract (URT) deposition of acetone and ethanol vapors, and to determine if deposition of these vapors could be described by a ventilation-perfusion (V-P) model, URT deposition efficiencies of these vapors were measured over a 12- to 18-min period at selected flow rates in the surgically isolated URT of urethane-anesthetized Fischer rats and Hartley guinea pigs. For both gases in both species, deposition efficiencies were significantly dependent upon inspiratory flow rate (p less than 0.0005). The V-P model predicts a linear relationship will exist between the ratio of the deposited to the nondeposited fraction and the inverse of the inspiratory flow rate. Such relationships were observed for deposition of acetone (r = 0.93, p less than 0.0005) and ethanol vapors (r = 0.95, p less than 0.0005) in the guinea pig and for deposition of acetone vapor (r = 0.95, p less than 0.0005) in the rat. In contrast, a linear relationship was not observed for ethanol in the rat suggesting that deposition mechanism(s) differ for this vapor in this species. Despite the fact that the surface area of the URT of the guinea pig is greater than that of the rat, URT deposition of these vapors was as much as twice as efficient in the rat as in the guinea pig (p less than 0.0005). This effect was not due to different blood:air partition coefficients as they were identical in both species. In toto, these results suggest there may be important anatomic and/or physiologic differences in the URT of the Hartley guinea pig and Fischer rat. Such differences may have to be considered when comparing the response(s) of these species to toxic gases or when extrapolating data obtained from these species to the human.

The aminonucleoside (PA) of puromycin is nephrotoxic to rats but not to guinea pigs. That guinea pigs are resistant to PA-nephrotoxicity has been confirmed in the Hartley strain. The metabolic disposition of subcutaneoulsy administered PA in the rat and in the Hartley guinea pig has been determined with the aid of the 8- 14 C-labeled compound. Unchanged PA is the major urinary excretion product in both the rat and guinea pig 8 hr after PA administration, and allantoin represents the major end-product of metabolism. Guinea pigs, but not rats, excrete part of the PA-8- 14 C as 14 CO 2 . The monodemethylated analog of PA, viz., 6-methylamino-9-(3′-amino-3′-deoxy-β- d -ribofuranosyl)purine, is the major nucleoside metabolite in the urine of rats and guinea pigs. The rat demethylates PA to this monodemethylated analog in vivo at a rate approximately 4-fold greater than the guinea pig.

Forty-seven Hartley guinea pigs were exposed for 1 h to approximately 1-micrometer (mass median aerodynamic diameter) sulfuric acid aerosols at concentrations that ranged from 1.2 to 48.3 mg/m3. Ten animals (controls) were exposed to filtered room air only. Eight H2SO4-exposed animals exhibited marked increases in total pulmonary resistance and marked decreases in dynamic compliance. Four of these eight "responsive" animals died during exposure. All other H2SO4-exposed animals exhibited no major difference from controls and were termed nonresponsive. The proportion of responsive to nonresponsive animals increased with exposure concentration, but the magnitude of pulmonary function change was similar for all responsive animals regardless of concentration. Compared to nonresponders, responsive animals had higher preexposure values of tidal transpulmonary pressure excursions and total pulmonary resistance and lower values of dynamic compliance. Preexposure transpulmonary pressure excursions were positively correlated with minute volume only for nonresponsive animals; transpulmonary pressure excursions were positively correlated with total pulmonary resistance in responsive animals. The results suggest that the Hartley guinea pig reacts to inhaled H2SO4 with an essentially all-or-none airway constrictive response and that an animal's sensitivity to this response may be related to its preexposure airway caliber.

A carcinogen binding protein (CBP) that is implicated in controlling the expression of rat cytochrome P-450c which is closely associated with aryl hydrocarbon hydroxylase (AHH) was examined in hepatic and extrahepatic tissues of the neonatal and adult New Zealand White (NZW) rabbits, the hepatic tissue of the BALB/cJ and DBA/2J mice, Brown Norway rat, Golden Syrian hamster and Hartley guinea pig. These animals and tissues were examined in order to determine whether there was a correlation of CBP levels and the reported presence or absence of inducibility of AHH in these tissues. The CBP was found in hepatic and extrahepatic tissue of the NZW rabbit and the hepatic tissues of all animals except the Hartley guinea pig. The Hartley guinea pig may provide a useful animal with which to further examine the role of CBP in cytochrome induction. Since the CBP is not a tissue specific protein and because it is found in both neonatal and adult NZW rabbit tissue, the data suggests that the CBP is not the limiting factor in the tissue specific induction of cytochromes nor in developmentally controlled induction of cytochromes previously reported in the rabbit.

The fiber type profiles of hindlimb muscles in the Hartley guinea pig, Sprague-Dawley rat, cat, Galago senegalensis (lesser bushbaby) and Nycticebus coucang (slow loris) were estimated histochemically. Fibers were classified as fast oxidative glycolytic, fast glycolytic or slow oxidative according to their myosin adenosine triphosphatase, α-glycerophosphate dehydrogenase and reduced nicotinamide adenine dinucleotide diaphorase activities. It was found that the soleus and vastus intermedius muscles had the highest proportion of slow oxidative fibers in all five species, demonstrating the constancy of muscle fiber profiles dependent upon anatomical position and functional utilization. The tensor fascia latae and white vastus lateralis of the guinea pig were mostly fast glycolytic, while the red vastus lateralis of the guinea pig consisted of predominantly fast oxidative glycolytic fibers. The majority of muscles investigated in these five mammals were heterogeneous, having a wide range of percentages of the three fiber types.