Sustained release of locally delivered celecoxib provides pain relief for osteoarthritis: a proof of concept in dog patients.

OBJECTIVE: Drug delivery platforms that allow for gradual drug release after intra-articular administration have become of much interest as a treatment strategy for osteoarthritis (OA). The aim of this study was to investigate the safety and efficacy of an intra-articular sustained release formulation containing celecoxib (CXB), a cyclooxygenase-2 (COX-2) selective inhibitor. METHODS: Amino acid-based polyesteramide microspheres (PEAMs), a biodegradable and non-toxic platform, were loaded with CXB and employed in two in vivo models of arthritis: an acute inflammatory arthritis model in rats (n = 12), and a randomized controlled study in chronic OA dog patients (n = 30). In parallel, the bioactivity of sustained release of CXB was evaluated in monolayer cultures of primary dog chondrocytes under inflammatory conditions. RESULTS: Sustained release of CXB did not alleviate acute arthritis signs in the rat arthritis model, based on pain measurements and synovitis severity. However, in OA dog patients, sustained release of CXB improved limb function as objective parameter of pain and quality of life based on gait analysis and owner questionnaires. It also decreased pain medication dependency over a 2-month period and caused no adverse effects. Prostaglandin E2 levels, a marker for inflammation, were lower in the synovial fluid of CXB-treated dog OA patients and in CXB-treated cultured dog chondrocytes. CONCLUSION: These results show that local sustained release of CXB is less suitable to treat acute inflammation in arthritic joints, while safe and effective in treating pain in chronic OA in dogs.

Soluble and pelletable factors in porcine, canine and human notochordal cell-conditioned medium: implications for IVD regeneration.

During intervertebral disc (IVD) maturation, notochordal cells (NCs) are replaced by chondrocyte-like cells (CLCs) in the nucleus pulposus, suggesting that NCs play a role in maintaining tissue health. Affirmatively, NC-conditioned medium (NCCM) exerts regenerative effects on CLC proliferation and extracellular matrix (ECM) production. The aim of this study was to identify NC-secreted substances that stimulate IVD regeneration. By mass spectrometry of porcine, canine and human NCCM, 149, 170 and 217 proteins were identified, respectively, with 66 proteins in common. Mainly ECM-related proteins were identified, but also organelle-derived and membrane-bound vesicle proteins. To determine whether the effect of NCCM was mediated by soluble and/or pelletable factors, porcine and canine NCCM were separated into a soluble (NCCM-S; peptides and proteins) and pelletable (NCCM-P; protein aggregates and extracellular vesicles) fraction by ultracentrifugation, and tested on bovine and canine CLCs in vitro, respectively. In each model, NCCM-S exerted a more pronounced anabolic effect than NCCM-P. However, glycosaminoglycan (GAG) uptake from the medium into the carrier gel prevented more definite conclusions. While the effect of porcine NCCM-P on bovine CLCs was negligible, canine NCCM-P appeared to enhance GAG and collagen type II deposition by canine CLCs. In conclusion, porcine and canine NCCM exerted their anabolic effects mainly through soluble factors, but also the pelletable NCCM factors showed moderate regenerative potential. Although the regenerative potential of NCCM-P should not be overlooked, future studies should focus on unraveling the protein-based regenerative mechanism from NCCM produced from isolated NCs, e.g. by NCCM fractionation and pathway blocking studies.

The species-specific regenerative effects of notochordal cell-conditioned medium on chondrocyte-like cells derived from degenerated human intervertebral discs.

During intervertebral disc (IVD) maturation, the main cell type shifts from notochordal cells (NCs) to chondrocyte-like cells (CLCs). NCs secrete factors with regenerative potential, making them an interesting focus for regenerative treatments. During initial development, these strategies preferably employ non-human donors due to easy availability of their NC-rich nucleus pulposus (NP) tissue. To increase the success of translating these strategies for clinical application, this study aimed to delineate whether NC-secreted factors of different species have a regenerative effect on human CLCs. Human, canine and porcine NC-rich NP tissue and NC-conditioned medium (NCCM) were analysed biochemically and histologically. Human CLC micro-aggregates from degenerated IVDs were cultured in human, canine or porcine NCCM. Collagen, glycosaminoglycan (GAG) and DNA content was determined and histology was performed. Canine and porcine NPs were richer in NCs than human NPs. Human NPs contained the highest collagen content, whereas the DNA and GAG content of canine NPs was significantly higher than that of human or porcine NPs. NCCM from all species significantly increased the DNA and GAG content of the human CLC micro-aggregates. Porcine and canine NCCM were significantly more potent than human NCCM in inducing GAG deposition, whereas only human NCCM induced collagen type II production. Secreted factors from human, canine and porcine NC-rich NPs exerted regenerative effects on human CLCs, indicating a cross-species effect. Bioactive compound(s) are present in NCCM of different species that may reverse human IVD degeneration, supporting further research into strategies based on NC-technology employing canine or porcine models for their translation into humans.

Anatomic description of the basivertebral nerve and meningeal branch of the spinal nerve in the dog.

PURPOSE: The existence of the basivertebral nerve and meningeal branch of the spinal nerve has not been proven in dogs to date. The objectives of this study are to 1) determine whether dogs have a meningeal branch of the spinal nerve (MBSN) and a basivertebral nerve (BVN) and to (2) describe anatomical characteristics of these two nerves. Authors also put forward a discussion on the possible clinical relevance of these findings. MATERIAL AND METHODS: Dissections were performed on six embalmed dogs at the Veterinary Faculty of Barcelona with the use of stereomicroscopy and microsurgery equipment. RESULTS: The MBSN (grossly) and BVN (grossly and histologically) were identified in the cervical, thoracic, and lumbar region in all dog specimens. In addition, other small fibers (suspected nerves) entering the vertebral body through small foramina close to the end plates were identified. Histological examination of the tissues confirmed the presence of nerve fibers (myelinated and unmyelinated) in suspected BVN samples. Results of the present study indicated that dogs have BVNs. Also, suspected nerve fibers were identified among the epidural fat, running from the intervertebral foramina, that likely represent the MBSN. CONCLUSION: These findings open up the discussion on extrapolation of treatment options employed in human medicine for "low back pain", such as BVN ablation, which is discussed in this article. Further anatomic and clinical studies of the innervation for the vertebral body, periosteum, vasculature, dorsal longitudinal ligament and anulus fibrosus are necessary to elucidate possible anatomical variants and breed differences as well as potential clinical (e.g., therapeutic) relevance.

The catabolic-to-anabolic shift seen in the canine osteoarthritic cartilage treated with knee joint distraction occurs after the distraction period.

Background: Cartilage regenerative mechanisms initiated by knee joint distraction (KJD) remain elusive. Animal experiments that are representative for the human osteoarthritic situation and investigate the effects of KJD at consecutive time points could be helpful in this respect but are lacking. This study investigated the effects of KJD on the osteoarthritic joint of dogs on two consecutive timepoints. Methods: Osteoarthritis was bilaterally induced for 10 weeks in 12 dogs using the groove model. Subsequently, KJD was applied to the right hindlimb for 8 weeks. The cartilage, subchondral bone and synovial membrane were investigated directly after KJD treatment, and after 10 weeks of follow-up after KJD treatment. Macroscopic and microscopic joint tissue alterations were investigated using the OARSI grading system. Additionally, proteoglycan content and synthesis of the cartilage were assessed biochemically. RT-qPCR analysis was used to explore involved signaling pathways. Results: Directly after KJD proteoglycan and collagen type II content were reduced accompanied by decreased proteoglycan synthesis. After 10 weeks of follow-up, proteoglycan and collagen type II content were partly restored and proteoglycan synthesis increased. RT-qPCR analysis of the cartilage suggests involvement of the TGF-ß and Notch signalling pathways. Additionally, increased subchondral bone remodelling was found at 10 weeks of follow-up. Conclusion: While the catabolic environment in the cartilage is still present directly after KJD, at 10 weeks of follow-up a switch towards a more anabolic joint environment was observed. Further investigation of this timepoint and the pathways involved might elucidate the regenerative mechanisms behind KJD. The Translational Potential of this Article: Further elucidation of the regenerative mechanisms behind KJD could improve the existing KJD treatment. Furthermore, these findings could provide input for the discovery or improvement of other joint regenerative treatment strategies.

Synovial membrane-derived mesenchymal progenitor cells from osteoarthritic joints in dogs possess lower chondrogenic-, and higher osteogenic capacity compared to normal joints.

BACKGROUND: Synovial membrane-derived mesenchymal progenitor cells (SM-MPCs) are a promising candidate for the cell-based treatment of osteoarthritis (OA) considering their in vitro and in vivo capacity for cartilage repair. However, the OA environment may adversely impact their regenerative capacity. There are no studies for canine (c)SM-MPCs that compare normal to OA SM-MPCs, even though dogs are considered a relevant animal model for OA. Therefore, this study compared cSM-MPCs from normal and OA synovial membrane tissue to elucidate the effect of the OA environment on MPC numbers, indicated by CD marker profile and colony-forming unit (CFU) capacity, and the impact of the OA niche on tri-lineage differentiation. METHODS: Normal and OA synovial membrane were collected from the knee joints of healthy dogs and dogs with rupture of the cruciate ligaments. The synovium was assessed by histopathological OARSI scoring and by RT-qPCR for inflammation/synovitis-related markers. The presence of cSM-MPCs in the native tissue was further characterized with flow cytometry, RT-qPCR, and immunohistochemistry, using the MPC markers; CD90, CD73, CD44, CD271, and CD34. Furthermore, cells isolated upon enzymatic digestion were characterized by CFU capacity, and a population doublings assay. cSM-MPCs were selected based on plastic adherence, expanded to passage 2, and evaluated for the expression of MPC-related surface markers and tri-lineage differentiation capacity. RESULTS: Synovial tissue collected from the OA joints had a significantly higher OARSI score compared to normal joints, and significantly upregulated inflammation/synovitis markers S100A8/9, IL6, IL8, and CCL2. Both normal and OA synovial membrane contained cells displaying MPC properties, including a fibroblast-like morphology, CFU capacity, and maintained MPC marker expression over time during expansion. However, OA cSM-MPCs were unable to differentiate towards the chondrogenic lineage and had low adipogenic capacity in contrast to normal cSM-MPCs, whereas they possessed a higher osteogenic capacity. Furthermore, the OA synovial membrane contained significantly lower percentages of CD90+, CD44+, CD34+, and CD271+ cells. CONCLUSIONS: The OA environment had adverse effects on the regenerative potential of cSM-MPCs, corroborated by decreased CFU, population doubling, and chondrogenic capacity compared to normal cSM-MPCs. OA cSM-MPCs may be a less optimal candidate for the cell-based treatment of OA than normal cSM-MPCs.

Pituitary tumour types in dogs and cats.

Pituitary tumours are common in dogs and are being increasingly recognized in cats. Pituitary tumours are usually classified as adenomas and should only be classified as carcinomas when there is evidence of metastatic spread of the tumour, which is rare. Despite the benign nature of most pituitary tumours, they can still compress or invade neighbouring tissues. Pituitary tumours can be functional (hormonally active) or non-functional (hormonally silent). The aim of this review was to provide an overview of the different pituitary tumour types in dogs and cats that have been reported in the literature. In dogs, the most common pituitary tumour type is the corticotroph adenoma, which can cause pituitary-dependent hypercortisolism. In cats, the most common pituitary tumour is the somatotroph adenoma, which can cause hypersomatotropism, and the second-most common is the corticotroph adenoma. A lactotroph adenoma has been described in one dog, while gonadotroph, thyrotroph and null cell adenomas have not been described in dogs or cats. Hormonally silent adenomas are likely underdiagnosed because they do not result in an endocrine syndrome. Tools used to classify pituitary tumours in humans, particularly immunohistochemistry for lineage-specific transcription factors, are likely to be useful to classify canine and feline pituitary tumours of unknown origin. Future studies are required to better understand the full range of pituitary adenoma pathology in dogs and cats and to determine whether certain adenoma subtypes behave more aggressively than others. Currently, the mechanisms that underlie pituitary tumorigenesis in dogs and cats are still largely unknown. A better understanding of the molecular background of these tumours could help to identify improved pituitary-targeted therapeutics.

The dog as an animal model for DISH?

Diffuse idiopathic skeletal hyperostosis (DISH) is a systemic disorder of the axial and peripheral skeleton in humans and has incidentally been described in dogs. The aims of this retrospective radiographic cohort study were to determine the prevalence of DISH in an outpatient population of skeletally mature dogs and to investigate if dogs can be used as an animal model for DISH. The overall prevalence of canine DISH was 3.8% (78/2041). The prevalence of DISH increased with age and was more frequent in male dogs, similar to findings in human studies. In the Boxer breed the prevalence of DISH was 40.6% (28/69). Dog breeds represent closed gene pools with a high degree of familiar relationship and the high prevalence in the Boxer may be indicative of a genetic origin of DISH. It is concluded that the Boxer breed may serve as an animal model for DISH in humans.

The effects of foraminotomy and intervertebral distraction on the volume of the lumbosacral intervertebral neurovascular foramen: An ex vivo study.

Degenerative lumbosacral stenosis in dogs frequently involves L7-S1 foraminal stenosis and L7 nerve root compression. Surgical techniques to decompress the L7 nerve root include foraminotomy and intervertebral distraction. The objective of this study was to compare the effect of foraminotomy and intervertebral distraction on the total, cranial, and caudal compartmental volumes of the L7-S1 intervertebral neurovascular foramen (NF). CT images were obtained from eight canine lumbosacral (L5-CD1) specimens in the following sequential conditions: native spine (1), after dorsal laminectomy and partial discectomy of L7-S1 (2), after L7-S1 foraminotomy (3), after distraction with an interbody cage between L7 and S1 (4), after cage distraction stabilized with pedicle screw-rod fixation in neutral (5) and flexed position (6). The volume of the complete NF and its cranial and caudal subcompartments were calculated using the CT images and statistically compared between conditions. P < 0.05 was considered statistically significant. The volume of the complete NF was significantly increased after foraminotomy (mean ± standard deviation (146.8 ± 26.5%, P < 0.01) and after distraction (Condition 4, 121.0 ± 19.1%; Condition 5, 116.6 ± 29.3 %; Condition 6, 119.0 ± 21.8 %; P = 0.01) with no difference between the distraction conditions. Foraminotomy induced a significantly larger increase in total NF volume compared to distraction. Foraminotomy, but not distraction, induced a significant increase in volume of the cranial subcompartment (158.2 ± 33.2 %; P < 0.01). Foraminotomy is more effective in increasing the foraminal volume and especially the cranial subcompartment, which is where the L7 nerve root traverses the NF. Hence, foraminotomy may be more effective in decompressing the L7 nerve root.

Endocrine diseases in animals.

BACKGROUND: Several endocrine disorders that affect humans also occur as endocrinopathies in companion animals. Spontaneous endocrine disorders in animals may provide valuable information for their counterparts in human endocrinology. For example, the discovery of progesterone-induced growth hormone production in the mammary gland of dogs may have important consequences for understanding the pathogenesis of breast cancer in women. In addition, the majority of diabetic cats have a type of diabetes mellitus that closely resembles type 2 diabetes mellitus in humans and therefore may serve as an animal model for this disease in humans. This review describes several endocrine diseases in companion animals that are quite similar to those in humans and emphasizes their usefulness as spontaneous animal models for human endocrine disorders.

Cushing's disease in dogs and humans.

BACKGROUND: Cushing's disease (CD) is a common endocrinological disorder in dogs with an estimated incidence of 1 to 2 cases/1,000 dogs/year. This is in contrast to humans in whom CD is rare. The clinical presentation of CD, however, is highly similar between dogs and humans, with characteristic signs, such as abdominal obesity, weight gain, fatigue, muscle atrophy and skin changes. Canine CD may therefore serve as an animal model for human CD, especially since therapeutic canine hypophysectomy can generate substantial amounts of primary corticotroph adenoma tissue for in vitro research purposes. In a recent study, we found that dopamine (DA) D(2) and somatostatin (SS) receptor subtypes are well expressed in canine corticotroph adenomas, but there are some distinct differences compared with the expression profile observed in human CD. These differences need to be considered when using canine CD as a model to evaluate the efficacy of novel DA/SS compounds for potential use in human CD. CASE REPORT: This case involves an 8-year-old female dog that developed signs of exercise intolerance, muscle weakness and polyuria/polydipsia due to an adrenocorticotropic hormone-secreting pituitary adenoma. The dog underwent curative transsphenoidal hypophysectomy and has remained in complete remission in the 3.5 years since surgery.

Expression and functional analysis of dopamine receptor subtype 2 and somatostatin receptor subtypes in canine cushing's disease.

Cushing's disease (CD) is a severe disorder characterized by chronic hypercortisolism due to an ACTH-secreting pituitary adenoma. Transsphenoidal adenomectomy is the treatment of choice in humans with CD, but recurrences occur frequently. Finding an effective and safe medical treatment for CD may improve long-term clinical outcome. The recent demonstration of expression of somatostatin receptor subtypes (mainly sst5) and dopamine receptor subtype 2 (D2) in human corticotroph adenomas offers the possibility for medical treatment of CD with novel somatostatin analogs and dopamine agonists. Investigation of the effects of these drugs is hampered by the low incidence of CD in humans. Interestingly, CD is a frequent disorder in dogs with striking clinical similarities with CD in humans. Therefore, we investigated the expression and functional role of D2 and somatostatin receptors in corticotroph adenoma cells from 13 dogs with active CD that underwent therapeutic hypophysectomy and normal anterior pituitary cells from five dogs. Quantitative RT-PCR and immunohistochemistry revealed that both in CD and normal anterior pituitary, sst2 was the predominant receptor subtype expressed, whereas D2 was modestly expressed and sst5 was expressed only at very low levels. In primary cultures of canine adenomas (n = 7), the sst2-preferring agonist octreotide also showed the strongest ACTH-suppressive effects. In conclusion, canine corticotroph adenomas provide an interesting model to study CD, but differences in somatostatin and dopamine receptor expression between humans and dogs should be taken into account when using dogs with CD as a model to evaluate efficacy of novel somatostatin analogs and dopamine agonists for human CD.

Expression and mutation analysis of Tpit in the canine pituitary gland and corticotroph adenomas.

Pituitary-dependent hyperadrenocorticism (PDH) in dogs is caused by a pituitary corticotroph adenoma. Although PDH is a common disorder in dogs, little is known about the underlying pathogenesis. In the pituitary glands of humans and mice, the pro-opiomelanocortin (POMC)-expressing cell lineages, the corticotrophs and melanotrophs, have a specific marker in common, the T-box transcription factor Tpit (Tbx19), which is obligate for POMC expression. Tpit also regulates the late differentiation of the corticotrophs and melanotrophs, and therefore may contribute to the pathogenesis of the corticotroph adenomas. The aim of this study was to perform an expression and mutation analysis of Tpit in the normal canine pituitary and in corticotroph adenomas. The distribution of the Tpit protein in the pituitary gland was studied with immunohistochemistry and the expression of the gene with RT-PCR. The coding region of Tpit cDNA from 14 dogs with PDH was screened for mutations. Tpit was expressed in corticotroph and melanotroph cells of the normal and adenomatous canine pituitary, and remained present in non-adenomatous corticotrophs of pituitaries from PDH dogs. No tumor-specific mutation in the Tpit cDNA from the corticotroph adenomas was found. However, a missense polymorphism in the highly conserved DNA-binding domain, the T-box, was discovered in one dog. It is concluded that Tpit can be used as a reliable marker for the corticotroph and melanotroph cells in the canine pituitary tissue and that mutations in the Tpit gene are unlikely to play a major role in the pathogenesis of canine corticotroph adenomas.

Review and retrospective analysis of degenerative lumbosacral stenosis in 156 dogs treated by dorsal laminectomy.

The medical records of 156 dogs with degenerative lumbosacral stenosis (DLS) that underwent decompressive surgery were reviewed for signalment, history, clinical signs, imaging and surgical findings. The German Shepherd Dog (GSD) was most commonly affected (40/156, 25.6%). Pelvic limb lameness, caudal lumbar pain and pain evoked by lumbosacral pressure were the most frequent clinical findings. Radiography showed lumbosacral step formation in 78.8% (93/118) of the dogs which was associated with elongation of the sacral lamina in 18.6% (22/118). Compression of the cauda equina was diagnosed by imaging (epidurography, CT, or MRI) in 94.2% (147/156) of the dogs. Loss of the bright nucleus pulposus signal of the L7-S1 disc was found on T2-weighted MR images in 73.5% (25/34) of the dogs. The facet joint angle at L7-S1 was significantly smaller, and the tropism greater in GSD than in the other dog breeds. The smaller facet joint angle and higher incidence of tropism seen in the GSD may predispose this breed to DLS. Epidurography, CT, and MRI allow adequate visualization of cauda equina compression. During surgery, disc protrusion was found in 70.5% (110/156) of the dogs. Overall improvement after surgery was recorded in the medical records in 79.0% (83/105) of the dogs. Of the 38 owners that responded to questionnaires up to five years after surgery, 29 (76%) perceived an improvement.

The mRNA expression of PTTG1 is a strong prognostic indicator for recurrence after hypophysectomy in dogs with corticotroph pituitary adenomas.

Pituitary-dependent hypercortisolism (PDH) is a common endocrinopathy in dogs, but the promotors and initiators of the tumourigenesis of corticotroph pituitary adenomas remain unknown. Based on human data, we investigated mRNA expression of pituitary tumour transforming gene 1 (PTTG1) with quantitative RT-PCR in canine corticotroph pituitary adenomas. PTTG1 was overexpressed in adenomas approximately 3-fold. A strong association was observed between PTTG1 expression and disease-free interval; dogs with high PTTG1 expression had a significantly (4 times; P=0.02) shorter disease-free interval than dogs with low PTTG1 expression. This paper shows that PTTG1 expression is a negative prognosticator in relation to disease-free interval and recurrence in dogs undergoing transsphenoidal hypophysectomy as treatment for PDH.

Data on a rat infection model to assess porous titanium implant coatings.

A model is needed to study the effectiveness of different anti-bacterial coatings on complex metal implants in a bone environment. This article shares data on the design of porous titanium implants for intramedullary implantation in the proximal rat tibia. The implant length, diameter and porosity were optimized after testing on cadaveric specimens. This article shares data on which parameters are critical to establish a chronic implant infection in Sprague Dawley rats when using the new implant design. To this end, different strains of Staphylococcus aureus and inoculation doses were investigated.

Intradiscal delivery of celecoxib-loaded microspheres restores intervertebral disc integrity in a preclinical canine model.

Low back pain, related to degeneration of the intervertebral disc (IVD), affects millions of people worldwide. Clinical studies using oral cyclooxygenase-2 (COX-2) inhibitors have shown beneficial effects, although side-effects were reported. Therefore, intradiscal delivery of nonsteroidal anti-inflammatory drugs can be an alternative treatment strategy to halt degeneration and address IVD-related pain. In the present study, the controlled release and biologic potency of celecoxib, a selective COX-2 inhibitor, from polyesteramide microspheres was investigated in vitro. In addition, safety and efficacy of injection of celecoxib-loaded microspheres were evaluated in vivo in a canine IVD degeneration model. In vitro, a sustained release of celecoxib was noted for over 28 days resulting in sustained inhibition of inflammation, as indicated by decreased prostaglandin E2 (PGE2) production, and anti-catabolic effects in nucleus pulposus (NP) cells from degenerated IVDs on qPCR. In vivo, there was no evidence of adverse effects on computed tomography and magnetic resonance imaging or macroscopic evaluation of IVDs. Local and sustained delivery of celecoxib prevented progression of IVD degeneration corroborated by MRI, histology, and measurement of NP proteoglycan content. Furthermore, it seemed to harness inflammation as indicated by decreased PGE2 tissue levels and decreased neuronal growth factor immunopositivity, providing indirect evidence that local delivery of a COX-2 inhibitor could also address pain related to IVD degeneration. In conclusion, intradiscal controlled release of celecoxib from polyesteramide microspheres prevented progression of IVD degeneration both in vitro and in vivo. Follow-up studies are warranted to determine the clinical efficacy of celecoxib-loaded PEAMs in chronic back pain.

Controlled release of celecoxib inhibits inflammation, bone cysts and osteophyte formation in a preclinical model of osteoarthritis.

Major hallmarks of osteoarthritis (OA) are cartilage degeneration, inflammation and osteophyte formation. COX-2 inhibitors counteract inflammation-related pain, but their prolonged oral use entails the risk for side effects. Local and prolonged administration in biocompatible and degradable drug delivery biomaterials could offer an efficient and safe treatment for the long-term management of OA symptoms. Therefore, we evaluated the disease-modifying effects and the optimal dose of polyesteramide microspheres delivering the COX-2 inhibitor celecoxib in a rat OA model. Four weeks after OA induction by anterior cruciate ligament transection and partial medial meniscectomy, 8-week-old female rats (n = 6/group) were injected intra-articular with celecoxib-loaded microspheres at three dosages (0.03, 0.23 or 0.39 mg). Unloaded microspheres served as control. During the 16-week follow-up, static weight bearing and plasma celecoxib concentrations were monitored. Post-mortem, micro-computed tomography and knee joint histology determined progression of synovitis, osteophyte formation, subchondral bone changes, and cartilage integrity. Systemic celecoxib levels were below the detection limit 6 days upon delivery. Systemic and local adverse effects were absent. Local delivery of celecoxib reduced the formation of osteophytes, subchondral sclerosis, bone cysts and calcified loose bodies, and reduced synovial inflammation, while cartilage histology was unaffected. Even though the effects on pain could not be evualated directly in the current model, our results suggest the application of celecoxib-loaded microspheres holds promise as novel, safe and effective treatment for inflammation and pain in OA.

Giant cell tumor of the bone in a scarlet macaw (Ara macao).

A 6-mo-old female scarlet macaw (Ara macao) was presented after a 2-mo period of anorexia and weakness. The bird was reluctant to fly 1 wk before referral due to a painful left wing. Physical examination revealed a firm swelling around the left shoulder. On radiographs, the diaphysis and proximal metaphysis of the left scapula were radiolucent. Computer tomography revealed an osteolytic process, suggestive of a bone tumor, affecting the left scapula. Cytology of a fine needle aspiration biopsy of the mass showed erythrocytes, a proliferation of spindle-shaped mesenchymal cells, and multinucleated giant cells (osteoclasts) suggestive of a giant cell tumor. The left wing, including the scapula, was amputated. The bird showed a fast recovery but died 1 hr later. Findings during the pathological examination were compatible with shock due to blood loss. The shoulder process was characterized as a giant cell tumor. To our knowledge, this is the first complete report of a giant cell tumor of the bone in a bird.

Effect of a titanium cage as a stand-alone device on biomechanical stability in the lumbosacral spine of canine cadavers.

Degenerative lumbosacral stenosis is a common disease in dogs characterised by intervertebral disc herniation, loss of disc height and stenosis. Decompressive dorsal laminectomy and partial discectomy can cause spinal instability and worsen foraminal stenosis. Pedicle screw and rod fixation (PSRF) with an intervertebral body cage allows for distraction and restoration of disc height and restores foraminal apertures. The aim of this study was to evaluate the ex vivo biomechanical properties of a titanium intervertebral cage alone and in combination with PSRF in the lumbosacral spine of dogs. The range of motion, neutral zone, neutral zone stiffness and elastic zone stiffness of the lumbosacral joint (L7-S1) of nine canine cadavers were determined in flexion/extension, lateral bending and axial rotation for four conditions: (1) native (unmodified) spine; (2) dorsal laminectomy and discectomy; (3) stand-alone cage; and (4) cage in combination with PSRF. The intervertebral disc height decreased after dorsal laminectomy, but increased after insertion of the cage. Insertion of the stand-alone cage decreased the range of motion and neutral zone compared to the laminectomy-discectomy and increased neutral zone stiffness in all directions. The range of motion further decreased after PSRF. From a biomechanical point of view, the use of a stand-alone intervertebral cage is a potential alternative to dorsal fixation of the lumbosacral junction, since it increases spinal stability and restores disc height.