D M Visco

Merck, Whitehouse Station, NJ, United States

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Publications (42)153.93 Total impact

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    ABSTRACT: The dog is a common model for study of osteoarthritis (OA). Subjective histologic scoring systems have often served as the reference standard for presence and severity of OA. However, these scoring systems have perceived shortcomings. The system developed for this report attempts to address these shortcomings by providing a standardized methodology for global assessment of the joint, versatility and the potential for relative weighting of pathology, allowing for comparison among time points, studies, and centers, and critical analysis of the system's reliability. The proposed system for assessment of canine tissues appears to provide an effective method for global assessment of articular pathology in OA. The system is versatile, comprehensive, and reliable and appears to have advantages over conventional scoring systems.
    Osteoarthritis and Cartilage 10/2010; 18 Suppl 3:S66-79. · 4.26 Impact Factor
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    ABSTRACT: A series of betamethasone 17alpha-carbamates were designed, synthesized, and evaluated for their ability to dissociate the two main functions of the glucocorticoid receptor, that is, transactivation and transrepression, in rat cell lines. A number of alkyl substituted betamethasone 17alpha-carbamates were identified with excellent affinity for the glucocorticoid receptor (e.g., 7, GR IC(50) 5.1 nM) and indicated dissociated profiles in functional assays of transactivation (rat tyrosine aminotransferase, TAT, and rat glutamine synthetase, GS) and transrepression (human A549 cells, MMP-1 assay). Gratifyingly, the in-vivo profile of these compounds, for example, 7, also indicated potent anti-inflammatory activity with impaired effects on glucose, insulin, triglycerides, and body weight. Taken together, these results indicate that dissociated glucocorticoid receptor modulators can be identified in rodents.
    Bioorganic & medicinal chemistry 09/2008; 16(16):7535-42. · 2.82 Impact Factor
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    ABSTRACT: The p38 MAP kinase signal transduction pathway is an important regulator of proinflammatory cytokine production and inflammation. Defining the roles of the various p38 family members, specifically p38alpha and p38beta, in these processes has been difficult. Here we use a chemical genetics approach using knock-in mice in which either p38alpha or p38beta kinase has been rendered resistant to the effects of specific inhibitors along with p38beta knock-out mice to dissect the biological function of these specific kinase isoforms. Mice harboring a T106M mutation in p38alpha are resistant to pharmacological inhibition of LPS-induced TNF production and collagen antibody-induced arthritis, indicating that p38beta activity is not required for acute or chronic inflammatory responses. LPS-induced TNF production, however, is still completely sensitive to p38 inhibitors in mice with a T106M point mutation in p38beta. Similarly, p38beta knock-out mice respond normally to inflammatory stimuli. These results demonstrate conclusively that specific inhibition of the p38alpha isoform is necessary and sufficient for anti-inflammatory efficacy in vivo.
    Journal of Biological Chemistry 12/2007; 282(48):34663-71. · 4.65 Impact Factor
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    ABSTRACT: The incidence and severity of rheumatoid arthritis (RA) are reduced during pregnancy. Estradiol-17beta and relaxin (RLX), hormones of pregnancy, are implicated in decreased immune responsiveness. The aim of this study was to determine the effects of estrogen and RLX, alone or in combination, on the development of adjuvant-induced arthritis (AIA) in ovariectomized (OVX) Lewis rats. Arthritis was induced on day 0 by adjuvant injection in the left hind paw. Rats were treated with estradiol valerate (E), porcine RLX, E + RLX, or vehicle. Healthy OVX control animals were used for comparison. Treatment with RLX or E alone decreased adjuvant-induced inflammation in both the injected (primary) and noninjected (secondary) hind paws. Combined treatment with E and RLX was more effective than either hormone alone in blocking secondary paw inflammation. Furthermore, E plus RLX reduced changes to spleen and thymus weights induced by adjuvant injection. Both E and RLX alone decreased circulating tumor necrosis factor (TNF) alpha. The combination of E and RLX resulted in a greater decline in TNFalpha than treatment with either hormone alone. There was no effect of hormones on the proinflammatory cytokine, interleukin (IL)-1beta. The anti-inflammatory cytokine IL-10 increased in response to E and E plus RLX. In conclusion, combined therapy with E and RLX was more effective than either hormone alone in reducing chronic inflammation, joint changes, and high circulating TNFalpha associated with AIA in rats. Accordingly, these hormones could play a role in reducing RA-induced inflammation during pregnancy by an effect on the immune system.
    Journal of Pharmacology and Experimental Therapeutics 09/2007; 322(2):887-93. · 3.89 Impact Factor
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    ABSTRACT: A new sub-class of p38 inhibitors represented by 7-amino-naphthyridone have been discovered. Benchmark compound 16 potently inhibited p38 in vitro, was functionally active, and displayed excellent pharmacokinetic profiles in two animal species. Compound 16 reduced inflammation in animal disease models at EC(50) doses as low as 0.2mpk.
    Bioorganic & Medicinal Chemistry Letters 11/2006; 16(20):5468-71. · 2.34 Impact Factor
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    ABSTRACT: We describe the basis of a new design for a user-friendly and easily reproduced mercury-displacement plethysmograph. This system was validated using the rat adjuvant-induced arthritis model in female Lewis rats. Furthermore, 2 different caging systems were evaluated to ensure that caging did not have an effect on disease progression and severity. These groups were evaluated further under frequent- and infrequent-handling conditions. Housing had less effect on the amount of swelling seen during the disease than did the amount of handling. Frequent handling significantly reduced the degree of paw swelling. Frequently handled, arthritic rats housed 5 rats per cage in the Box B system also lost a biologically significant amount of weight by the end of the study. Therefore, we do not recommend housing more than 4 rats per cage under these conditions.
    Journal of the American Association for Laboratory Animal Science: JAALAS 06/2006; 45(3):45-50. · 1.15 Impact Factor
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    ABSTRACT: Objective. To examine the distribution of the 3-B-3(–) and 7-D-4 epitopes in proteoglycans from morphologically normal and osteoarthritic (OA) canine articular cartilage.Methods. Cartilage samples from the femurs of stable and destabilized stifle joints of 9 dogs that had undergone transection of the cranial cruciate ligament were examined by immunohistochemistry.Results. The 3-B-3(–) and 7-D-4 epitopes were expressed in the superficial zone of cartilage from the destabilized femorotibial joints in the early stages of developing OA. The staining patterns with these two antibodies differed, with 3-B-3(–) reactivity confined to the superficial and upper middle zones of the articular cartilage, and 7-D-4 reactivity more prominent in the matrix, extending into the deeper zones and increasing with progression of the lesion. Both epitopes were also expressed in the superficial and upper middle zones of areas peripheral to the lesions and were detectable before the loss of matrix and proteoglycans could be identified by histochemical staining with toluidine blue.Conclusion. In this study, the expression of atypical chondroitin sulfate proteoglycans was demonstrated in osteoarthritic canine cartilage, and the pattern of expression changed as the lesions progressed. The occurrence of 3-B-3(–) and 7-D-4 epitopes appears to be associated with changes in chondrocyte metabolism in the early stages of cartilage degeneration in experimental osteoarthritis.
    Arthritis & Rheumatology 12/2005; 36(12):1718 - 1725. · 7.48 Impact Factor
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    ABSTRACT: A reduction in the incidence and severity of rheumatoid arthritis is seen in pregnant women. Relaxin, a hormone of pregnancy, has been implicated in decreased immune responsiveness. Consequently, the effects of relaxin and estradiol valerate, alone or in combination, were assessed in the development of adjuvant-induced arthritis in the rat. Combination hormone therapy reduced adjuvant-induced paw inflammation. Radiographic analysis of the tarsal joints showed that estradiol valerate plus relaxin treatment minimized soft tissue damage and bone changes when compared to vehicle-treated arthritic controls. These results indicate that relaxin may be a factor in reducing inflammation during pregnancy.
    Annals of the New York Academy of Sciences 06/2005; 1041:481-5. · 4.38 Impact Factor
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    ABSTRACT: Objective It has long been proposed that stromelysin is one of the major degradative matrix metalloproteinases responsible for the loss of cartilage in rheumatoid arthritis (RA) and osteoarthritis (OA). This hypothesis was tested by examining the arthritic paws of stromelysin 1 (SLN1)-deficient mice for loss of cartilage and for generation of neoepitopes that would be indicative of aggrecan cleavage.Methods The SLN1 gene was inactivated in murine embryonic stem cells, and knockout mice deficient in SLN1 activity were bred onto the B10.RIII background. The incidence and severity of collagen-induced arthritis (CIA) were compared in wild-type and knockout mice. Paws from mice with CIA were examined for loss of cartilage and for proteoglycan staining, as well as for the generation of the neoepitope FVDIPEN341.ResultsSLN1-deficient mice developed CIA, as did the wild-type N2 mice. Histologic analyses demonstrated no significant differences among the B10.RIII, wild-type, and knockout mice in loss of articular cartilage and proteoglycan staining. No decrease in the FVDIPEN341 epitope was observed in the SLN1-deficient mice.Conclusion Disruption of the SLN1 gene neither prevents nor reduces the cartilage destruction associated with CIA. Moreover, SLN1 depletion does not prevent the cleavage of the aggrecan Asn341-Phe342 bond.
    Arthritis & Rheumatology 05/2004; 41(1):110 - 121. · 7.48 Impact Factor
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    ABSTRACT: We characterized the mean peak vertical forces (MFz) in five groups of dogs which underwent transection of the left anterior cruciate ligament (ACLT) or sham ACLT and ipsilateral dorsal root ganglionectomy or sham-ganglionectomy, and the relationship of these forces to the severity of osteoarthritis (previously reported) 72 weeks after arthrotomy. Group I (N=7) underwent ACLT; Group II (N=8) underwent ACLT followed 52 weeks later by ganglionectomy; Group III (N=7) underwent ganglionectomy followed 2 weeks later by ACLT; Group IV (N=7) underwent sham-ganglionectomy followed 2 weeks later by ACLT; Group V (N=8) underwent ganglionectomy followed 2 weeks later by sham-ACLT. The dogs were evaluated 2, 6, 12, 24, 52 and 72 weeks after arthrotomy. From 6 weeks after arthrotomy until death, the left hindlimb MFz in Group V was significantly greater (P< 0.05) than that in the other four groups. The MFz of all groups which underwent ACLT decreased after arthrotomy. While the MFz of Group III (very severe OA) was about 10-20% greater than that of Groups I, II and IV (mild OA) 6 and 12 weeks after ACLT, and generally about 5-10% greater subsequently, this difference was not statistically significant. The MFz of Group II returned to pre-ganglionectomy levels, rather than to baseline levels, following ganglionectomy. (1) since the ipsilateral limb of dogs with ganglionectomy+sham ACLT bore normal amounts of weight throughout most of the postsurgical period, and its knee did not develop OA, one cannot argue that the knee was protected from OA because the limb was not used; (2) the fact that the MFz of dogs which underwent ACLT+ganglionectomy returned to pre-ganglionectomy levels, rather than baseline, is consistent with the hypothesis that the unstable joint was protected from accelerated breakdown by a central nervous system that was reprogrammed by sensation from the unstable limb; (3) the slightly-but consistently-greater MFz of dogs which underwent ganglionectomy+ ACLT may contribute to the acceleration of OA in this model.
    Osteoarthritis and Cartilage 11/1999; 7(6):567-73. · 4.26 Impact Factor
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    ABSTRACT: Five gelatin phantoms were constructed to study the effect of matrical hydration on magnetic resonance imaging (MRI) signal intensity using a low-field strength imager. Water content of the phantoms ranged from 75 to 95% weight/weight. Signal intensity values of each phantom were measured using five imaging sequences: proton density, T1-weighted, T2-weighted, inversion recovery with short inversion time, and inversion recovery with long inversion time. There was significant positive correlation (p < .05) of signal intensity with differences in hydration using the T2-weighted sequence and the inversion recovery sequence with short inversion time. Significant negative correlations (p < .05) were found with T1-weighted imaging and the inversion recovery sequence with long inversion time. In a second part of the study, in vivo focal variations in MRI signal intensity were evaluated in a canine cranial cruciate ligament deficient model of osteoarthritis. Signal intensity measurements were obtained from multiple areas of articular cartilage to identify an initial stage in osteoarthritis that is characterized in part by increased hydration of articular cartilage. At 6 weeks post-transection of the cranial cruciate ligament, an increase in signal intensity was detected in the articular cartilage of the weight-bearing portion of the lateral femoral condyle and the caudal portion of the medial tibial condyle with T1-weighted imaging. The increase in signal intensity may reflect increased proteoglycan synthesis by chondrocytes that also occurs early in the pathogenesis of osteoarthritis.
    Veterinary Radiology &amp Ultrasound 01/1999; 40(1):27-35. · 1.41 Impact Factor
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    ABSTRACT: Investigation of furans, pyrroles and pyrazolones identified 3-pyridyl-2,5-diaryl-pyrroles as potent, orally bioavailable inhibitors of p38 kinase. 3-(4-pyridyl-2-(4-fluoro-phenyl)-5-(4-methylsulfinylphenyl)-pyrrol e (L-167307) reduces secondary paw swelling in the rat adjuvant arthritis model: ID50 = 7.4 mg/kg/b.i.d.
    Bioorganic & Medicinal Chemistry Letters 11/1998; 8(19):2689-94. · 2.34 Impact Factor
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    ABSTRACT: Six healthy adult male mongrel dogs underwent cranial cruciate ligament transection in the left stifle. Survey radiography of both stifles and low-field (0.064 T) MRI of the left stifle were performed preoperatively and at 2, 6, and 12 weeks postoperatively. Focal changes in signal intensity were seen with MRI in the subchondral bone of the medial tibial condyle at 2 and 6 weeks postoperatively. At 12 weeks postoperative, a cyst-like lesion was detected using MRI in the subchondral bone of the medial tibial condyle in 4 of 6 dogs and a less defined lesion at this site in the remaining 2 dogs. The cyst-like lesion was spherical in shape and showed typical characteristics of fluid with low signal intensity on T1-weighted images, high signal intensity on T2-weighted images and high signal intensity on inversion recovery images. The lesion was seen in the subchondral bone of the caudal medial and/or middle region of the tibial plateau slightly cranial to the insertion of the caudal cruciate ligament. No subchondral cysts were seen in the tibia on radiographs. Histopathologically, the tibia was characterized by a loose myxomatous phase of early subchondral cyst formation.
    Veterinary Radiology &amp Ultrasound 04/1998; 39(3):167 - 173. · 1.41 Impact Factor
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    ABSTRACT: Up-regulation of the inducible isoform of nitric oxide synthase (iNOS) was determined during the development of adjuvant-induced arthritis in the rat. iNOS enzymatic activity, measured in spleen tissue, appeared and increased coincidentally with the appearance and degree of paw swelling and joint destruction in this arthritis model, when measured on days 0 through 21 subsequent to inoculation of the rats with adjuvant. The increase in enzymatic activity was paralleled by an increase in the plasma nitrite/nitrate (NOx) level and the appearance of immunoreactive iNOS, as measured by Western immunoblot, in the spleens of these rats. Prophylactic administration of N-iminoethyl-L-lysine (L-NIL) completely abolished iNOS activity (plasma NOx elevation) and effectively reduced both the swelling and radiographic changes in the joint tissues of the noninjected paw measured on day 21. However, therapeutic administration of L-NIL beginning on day 14 had no effect on the inflammatory or arthritic changes measured on day 21, even though plasma NOx levels were reduced to that of the naive controls. These results suggest that iNOS may be involved with the initial stages of the immune response to adjuvant injection, but its product, NO, does not mediate the chronic inflammation and joint destruction which occur during the later phase in this model.
    Journal of Pharmacology and Experimental Therapeutics 03/1998; 284(2):714-21. · 3.89 Impact Factor
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    ABSTRACT: It has long been proposed that stromelysin is one of the major degradative matrix metalloproteinases responsible for the loss of cartilage in rheumatoid arthritis (RA) and osteoarthritis (OA). This hypothesis was tested by examining the arthritic paws of stromelysin 1 (SLN1)-deficient mice for loss of cartilage and for generation of neoepitopes that would be indicative of aggrecan cleavage. The SLN1 gene was inactivated in murine embryonic stem cells, and knockout mice deficient in SLN1 activity were bred onto the B10.RIII background. The incidence and severity of collagen-induced arthritis (CIA) were compared in wild-type and knockout mice. Paws from mice with CIA were examined for loss of cartilage and for proteoglycan staining, as well as for the generation of the neoepitope FVDIPEN341. SLN1-deficient mice developed CIA, as did the wild-type N2 mice. Histologic analyses demonstrated no significant differences among the B10.RIII, wild-type, and knockout mice in loss of articular cartilage and proteoglycan staining. No decrease in the FVDIPEN341 epitope was observed in the SLN1-deficient mice. Disruption of the SLN1 gene neither prevents nor reduces the cartilage destruction associated with CIA. Moreover, SLN1 depletion does not prevent the cleavage of the aggrecan Asn341-Phe342 bond.
    Arthritis & Rheumatology 02/1998; 41(1):110-21. · 7.48 Impact Factor
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    ABSTRACT: Low-field magnetic resonance imaging (MRI) was performed on the stifle joints of four normal adult mongrel dogs using a 0.064 Tesla scanner. Markers were placed on each stifle joint to serve as reference points for comparing gross sections with the images. A T1-weighted sequence was used to image one stifle joint on each dog in the sagittal plane and the other stifle joint in the dorsal plane. The dogs were euthanized immediately following MRI and the stifle joints frozen intact. Each stifle joint was then embedded in paraffin, again frozen, and sectioned using the markers as reference points. On T1-weighted images, synovial fluid had low signal intensity (dark) compared to the infrapatellar fat pad which had a high signal intensity (bright). Articular cartilage was visualized as an intermediate bright signal and was separated from trabecular bone by a dark line representing subchondral bone. Menisci, fibrous joint capsule, and ligamentous structures appeared dark. In the true sagittal plane, the entire caudal cruciate ligament was often seen within one image slice. The patella was visualized as an intermediate bright signal (trabecular bone) surrounded by a low intensity signal (cortical bone). The trochlea and the intercondylar notch were difficult areas to analyze due to signal volume averaging of the curved surface of these areas and the presence of several types of tissues.
    Veterinary Radiology &amp Ultrasound 01/1998; 39(2):87-97. · 1.41 Impact Factor
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    ABSTRACT: To analyze the roles of two classes of proteinases, 'aggrecanase', and matrix metalloproteinases (MMPs), in chondrodestruction during murine collagen-induced arthritis (CIA). Generation of the 'aggrecanase' neo-epitope (NITEGE373), and the MMP neo-epitope (VDIPEN341) within aggrecan was studied by immunoperoxidase microscopy using specific anti-peptide antibodies in normal and stromelysin-1 (SLN-1) deficient knockout mice with CIA. High levels of NITEGE373 and VDIPEN341 neo-epitopes were observed in foci within CIA paw articular cartilage exhibiting depletion of glycosaminoglycans, in advance of significant cartilage erosion. The highest concentrations of NITEGE373 and VDIPEN341 labeling were observed and often co-distributed in the chondrocyte pericellular matrix, suggesting that stimulated chondrocytes can synthesize and/or activate both enzymes. Other regions of the cartilage frequently exhibited either NITEGE373 or VDIPEN341 labeling, but not both neo-epitopes simultaneously, suggesting that 'aggrecanase' and MMP cleavages of aggrecan may be generated independently. No detectable differences were observed in expression or distribution of either neo-epitope in SLN-1 knockout versus wild-type mice. In addition, in vitro digestion of joint sections with SLN-1 did not alter the expression of cartilage NITEGE373, while markedly increasing VDIPEN341 labeling. Peripheral nerves and brains of naive mice also exhibited intense anti-NITEGE373 labeling. These data indicate that NITEGE373 and VDIPEN341 aggrecan neo-epitopes are sensitive and specific markers of early joint pathology, and are consistent with the hypothesis that SLN-1 does not have 'aggrecanase' activity, and that 'aggrecanase' is distinct from the MMPs which cleave aggrecan at the MMP site.
    Osteoarthritis and Cartilage 11/1997; 5(6):407-18. · 4.26 Impact Factor
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    ABSTRACT: Carboxyalkyl peptides containing a biphenylylethyl group at the P1' position were found to be potent inhibitors of stromelysin-1 (MMP-3) and gelatinase A (MMP-2), in the range of 10-50 nM, but poor inhibitors of collagenase (MMP-1). Combination of a biphenylylethyl moiety at P1', a tert-butyl group at P2', and a methyl group at P3' produced orally bioavailable inhibitors as measured by an in vivo model of MMP-3 degradation of radiolabeled transferrin in the mouse pleural cavity. The X-ray structure of a complex of a P1-biphenyl inhibitor and the catalytic domain of MMP-3 is described. Inhibitors that contained halogenated biphenylylethyl residues at P1' proved to be superior in terms of enzyme potency and oral activity with 2(R)-[2-(4'-fluoro-4-biphenylyl)ethyl]-4(S)-n-butyl-1,5-pentane dioic acid 1-(alpha(S)-tert-butylglycine methylamide) amide (L-758,354, 26) having a Ki of 10 nM against MMP-3 and an ED50 of 11 mg/kg po in the mouse pleural cavity assay. This compound was evaluated in acute (MMP-3 and IL-1 beta injection in the rabbit) and chronic (rat adjuvant-induced arthritis and mouse collagen-induced arthritis) models of cartilage destruction but showed activity only in the MMP-3 injection model (ED50 = 6 mg/kg iv).
    Journal of Medicinal Chemistry 04/1997; 40(6):1026-40. · 5.61 Impact Factor
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    ABSTRACT: To quantify the matrix metalloproteinase-induced neoepitope F(M/V)DIPEN (Phe-[Met/Val]-Asp-Ile-Pro-Glu-Asn341) in guinea pig and rabbit cartilage during aging. Cartilage was taken from the stifle joint, nasal septum, and xiphoid process in guinea pigs and rabbits at selected ages. The cartilage was then extracted and evaluated for F(M/V)DIPEN levels by radioimmunoassay. In the 3 tissues studied, there were major increases in F(M/V)DIPEN levels during skeletal maturation and aging in both the guinea pig and rabbit cartilage. Except for spontaneous osteoarthritis that develops in guinea pigs with aging, increases in the neoepitope were not correlated with arthritis pathology. Increases in the level of F(M/V)DIPEN in cartilage occur as a result of skeletal maturation and aging. This physiologic accumulation of F(M/V)DIPEN in cartilage should be considered when using the neoepitope as a disease marker in arthritis.
    Arthritis & Rheumatology 08/1996; 39(7):1234-7. · 7.48 Impact Factor
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    ABSTRACT: The gross morphology of the musculus articularis genus and the location of muscle spindles at its point of insertion were studied in 18 adult dogs. The m. articularis genus was usually small and bipartite. From its originate on the cranial surface of the distal femur, it passed distally to terminate at the femoropatellar-joint capsule surface and extend into the synovial membrane. Although the m. articularis genus was usually composed of two parts, only a medial part was present in some dogs and was entirely absent in one specimen. Innervation to the m. articularis genus was provided by a branch of the femoral nerve. Muscle spindles were abundant in the termination of the muscle. spindles were abundant in the termination of the muscle. Frequently, the spindles were not in contact with muscle fibers (dissociated). Muscle spindles were located in close proximity to the surface of the synovial membrane. Morphological adaptations of the m. articularis genus support its potential function as a monitor of joint movement rather than an extensor of the stifle joint.
    Anantomia Histologia Embryologia 07/1996; 25(2):113-6. · 0.88 Impact Factor

Publication Stats

1k Citations
153.93 Total Impact Points

Institutions

  • 2006–2008
    • Merck
      • Department of Medicinal Chemistry
      Whitehouse Station, NJ, United States
  • 2005
    • University of North Carolina at Chapel Hill
      North Carolina, United States
  • 1998–1999
    • West Haven University
      West Haven, Connecticut, United States
  • 1994–1999
    • Auburn University
      • • Department of Anatomy, Physiology and Pharmacology
      • • College of Veterinary Medicine
      Auburn, AL, United States
  • 1989–1991
    • Purdue University
      • Department of Veterinary Clinical Sciences (VCS)
      West Lafayette, IN, United States