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Biomedical subjects

James L Cook

Publications and source records attributed to James L Cook.

At least 19 recordsLinked to original sources
PubMed2007

The interaction of adenovirus E1A with p300 family members modulates cellular gene expression to reduce tumorigenicity.

The use of adenovirus serotype 2 or 5 (Ad2/5) E1A as therapy for human malignancy requires an understanding of the mechanisms involved in E1A-induced tumor suppression. The prevailing use of E1A in the treatment of human malignancy stresses the non-immunologically mediated, anti-tumorigenic activities of E1A. However, the capacity of E1A to elicit a NK-cell and T-cell anti-tumor immune response and to sensitize tumor cells to lysis by immune effector molecules utilized by NK cells and T cells is also an important component of the anti-tumorigenic activity of E1A. This immune-mediated anti-tumorigenic activity of E1A is not shared by functionally similar viral oncoproteins such as the human papillomavirus type 16 (HPV16) E7 oncoprotein and is dependent on the capacity of E1A to interact with transcriptional coadapter, p300. To further define the molecular mechanisms whereby E1A reduces tumorigenicity, we compared total cellular gene expression in H4 cells, a human fibrosarcoma cell line, to gene expression in H4 cells stably expressing E1A, E7, or mutant forms of E1A that do not bind p300. The expression of E1A, but not E7, in H4 cells modulated the expression of cellular genes that may promote apoptosis, enhance immunogenicity and reduce tumor cell metastasis. The difference in the ability of E1A and E7 to modulate the expression of cellular genes that may influence tumorigenicity was largely attributable to distinct interactions of E1A and E7 with p300. Results of this study will be useful in designing novel strategies to augment the anti-tumorigenic activities of E1A.

Adenovirus E1A Proteins↗
PubMed2007

Use of three-dimensional computed tomography for diagnosis and treatment planning for open-mouth jaw locking in a cat.

CASE DESCRIPTION: A 2.5-year-old spayed female Persian cat was evaluated for acute inability to close its mouth. CLINICAL FINDINGS: A wry-mouth malocclusion was evident, and the right side of the mandible was longer than the left side. The right mandibular tooth row appeared to be lowered. The lower jaw was persistently maintained in an open position. The presumptive diagnosis was open-mouth jaw locking. Diagnostic imaging with computed tomography and 3-dimensional reconstruction was performed for definitive diagnosis and to achieve a better understanding of the lesions. Imaging revealed locking of the right ramus of the mandible, which was displaced ventrolaterally, causing the coronoid process to impinge on the right zygomatic arch. TREATMENT AND OUTCOME: A bilateral partial ostectomy of the rostroventral margins of the zygomatic arches with an autogenous fat graft implantation was performed. The cat recovered without complications and by the following morning was bright, alert, and responsive and eating canned cat food comfortably. One year after surgery, the owner reported that the cat had continued to function well, was eating normally, and had not had any observed locking episodes since surgery. CLINICAL RELEVANCE: Unlike radiographic imaging, computed tomography may be used to create 3-dimensional reconstructions of structures in cases of suspected open-mouth jaw locking; improve evaluation of the lesions; and improve decision-making and client education for diagnosis, treatment options, and prognosis.

Animals↗
PubMed2007

Evaluation of a novel biomaterial for intrasubstance muscle laceration repair.

The authors compare the effects of small intestinal submucosa (SIS) treatment to suture repair with respect to histologic and functional outcomes for complete muscle lacerations in a rabbit model. The authors hypothesized that SIS treatment of full-thickness muscle belly lacerations would significantly improve muscle function, strength, and regeneration compared to the current standard-of-care treatment. Muscle belly lacerations were created in the extensor digitorum longus (EDL) of both hind limbs of each rabbit. After randomization, lacerations were left unrepaired (n = 48) or repaired using a 4-0 Prolene modified Kessler stitch (n = 48). A flap of SIS graft was sutured into half (n = 24 each) of the repaired and unrepaired muscles forming four study groups. Suture repair with SIS augmentation of complete muscle lacerations resulted in healed tissue that most closely resembled normal muscle in terms of morphology and function when compared to current standard-of-care treatments. Active force production in this group reached 79% of uninjured controls 12 weeks after surgery. SIS may have important clinical advantages over suture repair alone and warrants further clinical study.

Animals↗
PubMed2006

Site-specific analysis of gene expression in early osteoarthritis using the Pond-Nuki model in dogs.

BACKGROUND: Osteoarthritis (OA) is a progressive and debilitating disease that often develops from a focal lesion and may take years to clinically manifest to a complete loss of joint structure and function. Currently, there is not a cure for OA, but early diagnosis and initiation of treatment may dramatically improve the prognosis and quality of life for affected individuals. This study was designed to determine the feasibility of analyzing changes in gene expression of articular cartilage using the Pond-Nuki model two weeks after ACL-transection in dogs, and to characterize the changes observed at this time point. METHODS: The ACL of four dogs was completely transected arthroscopically, and the contralateral limb was used as the non-operated control. After two weeks the dogs were euthanatized and tissues harvested from the tibial plateau and femoral condyles of both limbs. Two dogs were used for histologic analysis and Mankin scoring. From the other two dogs the surface of the femoral condyle and tibial plateau were divided into four regions each, and tissues were harvested from each region for biochemical (GAG and HP) and gene expression analysis. Significant changes in gene expression were determined using REST-XL, and Mann-Whitney rank sum test was used to analyze biochemical data. Significance was set at (p < 0.05). RESULTS: Significant differences were not observed between ACL-X and control limbs for Mankin scores or GAG and HP tissue content. Further, damage to the tissue was not observed grossly by India ink staining. However, significant changes in gene expression were observed between ACL-X and control tissues from each region analyzed, and indicate that a unique regional gene expression profile for impending ACL-X induced joint pathology may be identified in future studies. CONCLUSION: The data obtained from this study lend credence to the research approach and model for the characterization of OA, and the identification and validation of future diagnostic modalities. Further, the changes observed in this study may reflect the earliest changes in AC reported during the development of OA, and may signify pathologic changes within a stage of disease that is potentially reversible.

Journal Article↗
PubMed2006

A mutant allele of BARA/LIN-9 rescues the cdk4-/- phenotype by releasing the repression on E2F-regulated genes.

It has been proposed that C. elegans LIN-9 functions downstream of CDK4 in a pathway that regulates cell proliferation. Here, we report that mammalian BARA/LIN-9 is a predominantly nuclear protein that inhibits cell proliferation. More importantly, we demonstrate that BARA/LIN-9 also acts downstream of cyclin D/CDK4 in mammalian cells since (i) its antiproliferative effect is partially blocked by coexpression of cyclin D1, and (ii) a mutant form that lacks the first 84 amino acids rescues several phenotypic alterations observed in mice null for cdk4. Interestingly, mutation of BARA/LIN-9 restores the expression of E2F target genes in CDK4 null MEFs, indicating that the wild-type protein plays a role in the expression of genes required for the G1/S transition.

Alleles↗
PubMed2006

Evaluation of small intestinal submucosa grafts for meniscal regeneration in a clinically relevant posterior meniscectomy model in dogs.

Large meniscal defects are a common problem for which treatment options are limited. Successful meniscal regeneration has been achieved by using grafts of small intestinal submucosa in posterior, vascular meniscal defects in a dog model. This study investigates the long-term effects of a tibial tunnel fixation technique and a clinically based meniscectomy defect on meniscal regeneration using this model. Eight mongrel dogs underwent medial arthrotomy and partial meniscectomy. The dogs were divided into groups based on defect treatment: small intestinal submucosa (n = 4) or meniscectomy (n = 4). Dogs were scored for lameness by subjective scoring postoperatively, sacrificed at 6 months, and assessed for articular cartilage damage, gross and histologic appearance of the operated meniscus, amount of new tissue in the defect, and relative compressive stiffness of articular cartilage. Dogs in the meniscectomy group were significantly (P = .002) more lame than dogs treated with small intestinal submucosa. Small intestinal submucosa-treated joints had significantly (P = .01) less articular cartilage damage than meniscectomy joints. Small intestinal submucosa meniscal implants resulted in production of meniscal-like replacement tissue, which was consistently superior to meniscectomy in amount, type, and integration of new tissue, chondroprotection, and limb function during the study period. Small intestinal submucosa implants may be useful for treatment of large posterior vascular meniscal defects in humans. The tibial tunnel technique used for fixation may have clinical advantages and therefore warrants further investigation.

Animals↗
PubMed2006

Effects of dynamic compressive load on collagen-based scaffolds seeded with fibroblast-like synoviocytes.

Synoviocytes have been speculated to play potential reparative and remodeling roles in vascular meniscal injuries. In addition, synoviocytes may mediate the transformation of intraarticularly placed collagen-based scaffolds into fibrocartilage through exposure to dynamic compressive loads. The objectives of this study were to assess the feasibility of using fibroblast-like synoviocytes (FLS) to engineer meniscal-like fibrocartilage and to better understand the mechanosensitivity of FLS by seeding them onto collagen scaffolds exposed to dynamic compressive loads. Canine FLS were seeded onto disks of four commercially available collagen-based scaffolds (Restore, Permacol, Cuff Patch, and Graff Jacket) and subjected either to one of two levels of intermittent dynamic compressive load or no load. The disks were harvested at 1 and 2 weeks and assessed for cell viability, retention, and infiltration, as well as extracellular matrix production. In general, loading regimens decreased cellularity, and nonloaded Restore grafts retained the most cells across time intervals. Spatial distribution of FLS was optimized in Restore grafts and was overall better in non-crosslinked collagen scaffolds (Restore and Graft Jacket) than cross-linked matrices. Collagen production was noted in association with penetrating FLS clusters in the Restore scaffolds only. The applied biomechanical stimulus did not appear to induce fibrochondrogenesis in any treatment group. These data suggest that Restore scaffolds may foster greater cell retention and infiltration when compared to other commercially available, collagen-based biomatrices.

Animals↗
PubMed2006

Principles of uniapical and biapical radial deformity correction using dome osteotomies and the center of rotation of angulation methodology in dogs.

OBJECTIVE: To describe the normal anatomic axis of the canine radius in 2 planes (frontal, sagittal), and report the use and efficacy of dome osteotomies for acute correction of canine antebrachial deformities. STUDY DESIGN: Retrospective study. SAMPLE POPULATION: Normal antebrachii (n = 20) radiographs were used as a reference, and 7 dogs with 9 radial angular limb deformities that were corrected by use of dome osteotomies. METHODS: Orthogonal radiographs of 20 normal antebrachii were used to determine normal ranges of frontal (FPA) and sagittal plane anatomic axes (SPA). Pre and postoperative radiographs of 7 dogs (9 radii) that had surgical correction of radial angular limb deformities by dome osteotomies were reviewed. Success at deformity correction into established normal ranges and to the normal contralateral side, if present, was determined. RESULTS: Normal ranges were FPA, 0-8 degrees and SPA, 8-35 degrees . There were 4 biapical and 5 uniapical deformities. FPA and SPA were corrected into normal range in 66% and 78% of affected limbs, respectively; however, only 44% of radii were corrected into normal ranges in both planes. CONCLUSIONS: Ranges for normal canine radial axes can be used as goals for angular limb correction when there is bilateral angular deformity. The dome osteotomy technique is advantageous in certain conditions for biplanar deformity correction. CLINICAL RELEVANCE: Dome osteotomies can be used to correct radial deformities in the frontal and sagittal planes, with certain advantages, but are heavily reliant on appropriate preoperative planning.

Animals↗
PubMed2006

Effect of meniscal release on rate of subsequent meniscal tears and owner-assessed outcome in dogs with cruciate disease treated with tibial plateau leveling osteotomy.

OBJECTIVE: To determine and compare rates of meniscal tears after tibial plateau leveling osteotomy (TPLO) among 3 groups of dogs based on treatment method: arthrotomy with meniscal release (openR), arthrotomy without meniscal release (openNR), arthroscopy without meniscal release (scopeNR), and compare long term owner-assessed outcomes for the same groups. STUDY DESIGN: Retrospective cohort study. SAMPLE POPULATION: Stifles (n=254) of dogs that had TPLO. METHODS: The three groups were compared for significant (P<.05) differences in rate of subsequent tears using a chi(2) test. Odds ratios for likelihood of subsequent meniscal tears were determined. Data for signalment, outcome, time to peak function, and time to subsequent tear were compared for significant differences using ANOVA, t-test, or rank sum test. RESULTS: Subsequent meniscal tears were diagnosed in 16 cases (6.3%). Of dogs with subsequent meniscal tears, 9 had openNR, 4 had openR, and 3 had scopeNR; the proportion of subsequent meniscal tears was significantly different (P=.035) among groups. Odds ratio indicated that subsequent meniscal tear was 3.8 times more likely to occur for openNR than openR or scopeNR. No significant differences among groups were noted for measures of outcome. CONCLUSIONS: Meniscal release did not reduce the rate of subsequent meniscal tears when compared with cases treated arthroscopically or when compared with all cases combined, but may be advantageous when meniscal pathology cannot be comprehensively assessed in the cranial cruciate deficient stifle. Meniscal release had no effects on owner-assessed outcome as determined in this study. CLINICAL RELEVANCE: The low rates of subsequent meniscal tears in conjunction with the relatively high and equivocal levels of owner-assessed outcome and time to peak function for all 3 treatment groups suggest that any of these surgical management strategies can be considered acceptable. We suggest that a meniscal release be performed when complete and thorough exploration of the joint and meniscus cannot be, or are not, performed.

Analysis of Variance↗
PubMed2006

Enhanced fracture and soft-tissue healing by means of anabolic dietary supplementation.

BACKGROUND: Malnutrition is common in hospitalized injured patients. It contributes to delayed fracture-healing and increased morbidity. However, relatively little attention has been directed toward nutritional strategies for augmenting musculoskeletal recovery after a fracture. This animal study was designed to examine the effects of dietary protein intake and the role of conditionally essential amino acids in muscle and bone-healing after a fracture. METHODS: One hundred adult male rats were used. Ten rats served as controls and received a 15% protein diet throughout the study. The remaining ninety rats received a 6% protein diet for five weeks to induce protein malnutrition. The rats underwent intramedullary nailing and closed midshaft fracture of one femur. After the fracture, they were separated into three isocaloric dietary groups. Group P6 received a diet with 6% protein; Group P15, a diet with 15% protein; and group P30, a diet with 30% protein with conditionally essential amino acids. At two, four, and six weeks after surgery, ten animals from each group were killed and the femora were evaluated with dual x-ray absorptiometry, histomorphometric assessment of callus, and torsional testing. The quadriceps muscles were analyzed for total mass, total protein content, and for mRNA expression of insulin-like growth factor-1 (IGF-1), IGF-2, IGF receptors, actin, myosin, and vascular endothelial growth factor (VEGF). RESULTS: The P30 group demonstrated elevations in albumin, body mass, muscle mass, total protein content of muscle, and bone mineral density in the fracture callus compared with the P6 diet group at six weeks (p < 0.05). Molecular analysis of muscle revealed that IGF-1, IGF-2, IGF receptors, myosin, actin, and VEGF gene expression were significantly (p < 0.001) higher in the P6 group compared with the P30 group. Biomechanical testing of the femora, however, showed no significant differences. CONCLUSIONS: Dietary supplementation with conditionally essential amino acids in malnourished animals had anabolic effects on bone mineralization, body mass, and muscle mass.

Absorptiometry, Photon↗
PubMed2005

Comparison of arthroscopic and radiographic abnormalities in the hip joints of juvenile dogs with hip dysplasia.

OBJECTIVE: To compare radiographic and arthroscopic abnormalities in juvenile dogs with clinically apparent hip dysplasia. DESIGN: Case series. ANIMALS: 52 dogs (70 hip joints) with clinical signs of hip dysplasia scheduled to undergo triple pelvic osteotomy. PROCEDURE: A ventrodorsal radiographic projection of the pelvis was evaluated by a radiologist unaware of clinical and arthroscopic findings, and radiographic osteoarthritic abnormalities were judged and scored as absent (0), mild (1), moderate (2), or severe (3). Arthroscopy was performed by a surgeon unaware of clinical and radiographic findings, and arthroscopic abnormalities were graded from 0 (normal) to 5 (exposed, eburnated subchondral bone). RESULTS: In 30 of the 70 (43%) hip joints, no radiographic osteoarthritic abnormalities were seen. Severe, full-thickness articular cartilage lesions (grade 4) of the femoral head or acetabulum were seen arthroscopically in 14 (20%) joints. Lesions > or = grade 2 were seen in 60 (86%) joints. Partial tearing of the ligament of the femoral head was present in 57 (81%) joints, and complete rupture was seen in 5 (7%). Radiographic abnormalities were seen in 13 of the 14 (93%; 95% confidence interval, 66% to 99.8%) joints with grade 4 arthroscopic abnormalities but in only 23 of the 46 (50%; 95% confidence interval, 35% to 65%) joints with grade 2 or 3 arthroscopic abnormalities. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that radiography is not a sensitive method for identifying moderate cartilage lesions in juvenile dogs with hip dysplasia. If moderate cartilage lesions are an important prognostic indicator for the success of triple pelvic osteotomy, then methods other than radiography should be used to detect these lesions.

Animals↗
PubMed2005

Long-term outcome for large meniscal defects treated with small intestinal submucosa in a dog model.

BACKGROUND: Large meniscal defects are a common problem for which current treatment options are limited. HYPOTHESIS: Treatment of posterior medial meniscal defects in dogs with small intestinal submucosa is superior to partial meniscectomy in terms of clinical limb function, chondroprotection, and amount and type of new tissue in the defect. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 51 mongrel dogs underwent medial arthrotomy with creation of standardized meniscal defects. The dogs were divided into groups based on defect treatment: small intestinal submucosa meniscal implant (n = 29) or meniscectomy (n = 22). The dogs were assessed for lameness by subjective scoring after surgery and sacrificed at 3, 6, or 12 months and assessed for articular cartilage damage, gross and histologic appearance of the operated meniscus, amount of new tissue in the defect, equilibrium compressive modulus of meniscal tissue, and relative compressive stiffness of articular cartilage. RESULTS: Dogs in the meniscectomy groups were significantly (P < .001) more lame than dogs treated with small intestinal submucosa. Joints treated with small intestinal submucosa had significantly (P <.001) less articular cartilage damage, based on india ink staining, than did those treated with meniscectomy. Menisci receiving small intestinal submucosa had more tissue filling in the defects than did menisci receiving no implants, and this new tissue was more mature and meniscus-like and better integrated with remaining meniscus. CONCLUSION: Small intestinal submucosa scaffolds placed in large meniscal defects resulted in production of meniscus-like replacement tissue, which was consistently superior to meniscectomy in amount, type, and integration of new tissue; chondroprotection; and limb function in the long term. CLINICAL RELEVANCE: Small intestinal submucosa implants might be useful for treatment of large posterior vascular meniscal defects in humans.

Animals↗
PubMed2005

Adenovirus E1A gene-induced tumor cell rejection through cellular sensitization to immune and nonimmune apoptotic injuries.

The E1A gene of human adenovirus (Ad) serotypes 2 and 5 induces susceptibility of cells from several species, including human, to lysis by natural killer cells, activated macrophages and a variety of other immunologic and nonimmune cellular injuries. This E1A activity is the rationale behind some treatment strategies using combined adenoviral vector infection and chemotherapy for cancer. This review will consider the evolution of the studies that have resulted in the current understanding of the cellular mechanisms of E1A-induced tumor cell cytolytic susceptibility and sensitization to apoptotic injury. The translation of in vitro observations to experimental models testing E1A-induced tumor rejection in the context of the cellular immune response and E1A-induced sensitization of human tumor cells to therapeutic injuries will be discussed. Review of available information on the molecular mechanisms of E1A-induced cellular sensitivity to immune and nonimmune injuries will be used as a basis for consideration of possible future directions of this research.

Adenovirus E1A Proteins↗
PubMed2005

The current status of treatment for large meniscal defects.

Meniscal pathology causing loss of function is a common problem that requires treatment in a large number of individuals each year. A patient with a meniscal-deficient knee is doomed to the development of osteoarthritis, pain, and knee dysfunction. The amount, shape, and composition of meniscal tissue influence its function and, therefore, influence the health of the knee joint. When preservation of healthy meniscal tissue cannot be accomplished, methods for replacement or regeneration of meniscal tissue are necessary. This review article will discuss current methods of meniscal tissue replacement and regeneration and potential future modes of therapy.

Animals↗
PubMed2005

Effects of proinflammatory cytokines on canine articular chondrocytes in a three-dimensional culture.

OBJECTIVE: To determine the effects of interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha on canine chondrocytes cultured in an agarose-based 3-dimensional (3-D) system. SAMPLE POPULATION: Humeral head articular cartilage chondrocytes obtained from 6 adult dogs. PROCEDURE: Chondrocytes were cultured in a 3-D system for < or = 12 days in serum-free medium with IL 1alpha, IL-1beta, or TNF-alpha at concentrations of 20, 50, or 100 ng/mL. After 1, 3, 6, and 12 days, glycosaminoglycan (GAG) concentrations in 3-D constructs; nitric oxide and prostaglandin E2 (PGE2) concentrations in media samples; and relative expressions of selected genes, including metalloproteinase (MMP)-13 and tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2, were evaluated. Control specimens were comprised of chondrocytes cultured without proinflammatory cytokines. RESULTS: In control 3-D constructs, GAG content was significantly higher than for all other constructs. Compared with control values, relative expressions of MMP-13, TIMP-1, and TIMP-2 genes in the IL-1beta (50 ng/mL) group were significantly higher at day 1; at all evaluations, media concentrations of nitric oxide were significantly higher in all TNF-alpha-treated cultures; and concentrations of PGE2 in media samples were significantly higher in the IL-1beta (50 ng/mL) and IL-1beta (100 ng/mL) groups at days 1 and 3, in the IL-1beta (100 ng/mL) group at day 6, and in all TNF-alpha groups at days 1, 3, and 6. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that TNF-alpha more readily induces production of nitric oxide and PGE2 by canine chondrocytes, compared with IL-1beta. In vitro, IL-1alpha appeared to have a minimal effect on canine chondrocytes.

Aggrecans↗
PubMed2004

Serum amyloid A-activating factor-1 (SAF-1) transgenic mice are prone to develop a severe form of inflammation-induced arthritis.

The transcription factor serum amyloid A-activating factor-1 (SAF-1) has been identified as a regulator of a number of cellular genes. To assess the pleiotropic role of SAF-1 in vivo, we generated SAF-1 transgenic mice, in which CMV immediate-early promoter was used to direct expression of the SAF-1 transgene in multiple organs. Our study shows that overexpression of SAF-1 predisposes animals to arthritis. Although SAF-1 transgenic mice do not spontaneously develop arthritis, they develop a severe form of arthritis when challenged with the Lyme disease agent Borrelia burgdorferi, which is known to promote arthritis development in both humans and mice. CMV-SAF-1 transgenic mice, upon B. burgdorferi infection, showed increased joint swelling and synovial inflammation compared with nontransgenic littermates. Immunohistochemical analysis of joint tissues collected 21 days after B. burgdorferi infection revealed colocalization of matrix metalloproteinase-1, a degradative enzyme that destroys type II collagen, a major architectural component of articular cartilage, and SAF-1 in both SAF-1 transgenic and nontransgenic mice. Further analysis by RNase protection assay and Western immunoblot demonstrated the presence of higher levels of matrix metalloproteinase-1 and SAF-1 in the inflamed joints of SAF-1 transgenic mice compared with their levels in nontransgenic mice. Consistent with these findings, reduced levels of proteoglycans were detected in the inflamed joint cartilage of transgenic mice, indicating damage to the cartilage structure. Together these results suggest a role of SAF-1 in the pathogenesis of inflammation-induced arthritis.

Animals↗