Disease-Modifying Osteoarthritis Treatment With Interleukin-1 Receptor Antagonist Gene Therapy in Small and Large Animal Models.

OBJECTIVE: Gene therapy holds great promise for the treatment of osteoarthritis (OA) because a single intraarticular injection can lead to long-term expression of therapeutic proteins within the joint. This study was undertaken to investigate the use of a helper-dependent adenovirus (HDAd)-mediated intraarticular gene therapy approach for long-term expression of interleukin-1 receptor antagonist (IL-1Ra) as sustained symptomatic and disease-modifying therapy for OA. METHODS: In mouse models of OA, efficacy of HDAd-IL-1Ra was evaluated by histologic analysis, micro-computed tomography (micro-CT), and hot plate analysis. In a horse OA model, safety and efficacy of HDAd-IL-1Ra were evaluated by blood chemistry, analyses of synovial fluid, synovial membrane, and cartilage, and gross pathology and lameness assessments. RESULTS: In skeletally immature mice, HDAd-IL-1Ra prevented development of cartilage damage, osteophytes, and synovitis. In skeletally immature and mature mice, treatment with HDAd-interleukin-1 receptor antagonist post-OA induction resulted in improved-albeit not significantly-cartilage status assessed histologically and significantly increased cartilage volume, cartilage surface, and bone surface covered by cartilage as assessed by micro-CT. Fewer osteophytes were observed in HDAd-IL-1Ra-treated skeletally immature mice. Synovitis was not affected in skeletally immature or mature mice. HDAd-IL-1Ra protected against disease-induced thermal hyperalgesia in skeletally mature mice. In the horse OA model, HDAd-IL-1Ra therapy significantly improved lameness parameters, indicating efficient symptomatic treatment. Moreover, macroscopically and histologically assessed cartilage and synovial membrane parameters were significantly improved, suggesting disease-modifying efficacy. CONCLUSION: These data from OA models in small and large animals demonstrated safe symptomatic and disease-modifying treatment with an HDAd-expressing IL-1Ra. Furthermore, this study establishes HDAd as a vector for joint gene therapy.

Duodenoduodenostomy for obstruction of the sigmoid flexure of the duodenum in cattle.

OBJECTIVE: To describe clinical findings, surgical treatment, and outcome associated with duodenoduodenostomy for treatment of duodenal obstruction secondary to adhesions associated with the sigmoid flexure of the duodenum. STUDY DESIGN: Retrospective study (1996-2016). ANIMALS: Fourteen Holstein cattle. METHODS: Medical records of cows treated at 3 academic surgical referral centers with duodenoduodenostomy for duodenal obstruction secondary to adhesions associated with the sigmoid flexure of the duodenum were reviewed. Data that were collected included signalment, physical examination results, laboratory results, diagnostic findings, treatments, and survival to discharge. Owners were contacted for follow-up information. RESULTS: Affected cattle ranged in age from 4 months to 5 years. Electrolyte abnormalities, including severe hypochloremia, were present in all cases. Abnormalities included cranial duodenal distension without concurrent distension of the descending duodenum and palpable focal adhesions in the region of the sigmoid flexure of the duodenum. Duodenoduodenostomy involved a stapled (n = 11) or sutured (n = 3) side-to-side anastomosis between the cranial duodenum and descending duodenum. Thirteen of 14 cattle that were treated with duodenoduodenostomy survived to hospital discharge. Long-term follow-up was available in 8 cows, and 7 of those 8 survived for at least 1 year. CONCLUSION: Short- and long-term survival were favorable after duodenoduodenostomy in cattle with adhesions associated with the sigmoid flexure of the duodenum. CLINICAL SIGNIFICANCE: Duodenoduodenostomy results in acceptable survival and future productivity in cows with obstruction at the sigmoid flexure of the duodenum.

Effect of needle diameter on the viability of equine bone marrow derived mesenchymal stem cells.

OBJECTIVES: Mesenchymal stem cells (MSCs) are frequently delivered via needle injection for treatment of musculoskeletal injuries. The purpose of this study was to evaluate the effect of needle diameter on the viability of MSCs. METHODS: Equine bone marrow-derived MSCs from 5 horses were suspended in PBS, and held at room temperature for 7 hours to mimic shipping conditions. Two replicate samples for each needle size (20, 22, 23, or 25-gauge [ga]) were aspirated into a 3 mL syringe and re-injected into the holding vial 3 times, to reproduce the resuspension of cells prior to injection in clinical cases. Cells were stained with fluorescein diacetate and propidium iodide to measure viability. Flow cytometry (FC) was performed to compare cell debris and intact cells between groups. RESULTS: MSC viability was higher when cells were passed through a 20-ga rather than a 25-ga needle. Cell suspensions passed through a 20-ga needle contained a larger percentage of intact cells, compared to 25-ga samples. The percentage of debris present in cell suspensions tended to increase with decreasing needle diameter. Neither horse nor passage had a significant effect on viability. CONCLUSIONS: Cell damage is more likely when MSCs are passed through 25-ga rather than 20-ga needles. CLINICAL RELEVANCE: Use of needles larger than 25-ga is recommended to maintain the viability of MSCs injected in horses.

Arthroscopic removal of discrete palmar carpal osteochondral fragments in horses: 25 cases (1999-2013).

OBJECTIVE: To characterize discrete palmar carpal osteochondral fragmentation in horses and to document the effect of osteoarthritis and surgical removal of these fragments on functional outcome. DESIGN: Retrospective case series. ANIMALS: 25 horses. PROCEDURES: Medical records and radiographic views were reviewed to identify horses that had radiographic evidence of palmar carpal fragmentation, which was subsequently treated by arthroscopic removal. Information collected included cause of fracture, initial and long-term clinical and radiographic findings, and functional outcome. RESULTS: Palmar carpal fragmentation of 30 carpal bones was identified in 25 unilaterally affected horses. A known traumatic event was reported to cause the fragmentation in 17 of the 25 (68%) horses. Of the 25 horses, 17 (68%) had fragmentation involving the antebrachiocarpal joint, 7 (28%) had fragmentation involving the middle carpal joint, and 1 (4%) had fragmentation involving the carpometacarpal joint. The proximal aspect of the radial carpal bone was the most commonly affected site (12/30 fragments), followed by the accessory carpal bone (6/30). Of the 25 horses, 19 (76%) were not lame (sound) after surgery and returned to their intended use, 4 (16%) were considered pasture sound, and 2 were euthanized (because of severe postoperative osteoarthritis or long bone fracture during recovery from anesthesia). Eight of the 14 horses with preoperative evidence of osteoarthritis returned to function after surgery. Twelve of 17 horses with antebrachiocarpal joint fragments and 6 of 7 horses with middle carpal joint fragments returned to their previous use. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that the prognosis for horses after arthroscopic removal of palmar carpal osteochondral fragments is good. Early intervention, before the development of osteoarthritis, is recommended.

Laparoscopic-guided compared to skilled instructor support for student rectal examination training using live horses in the veterinary curriculum.

OBJECTIVES: To evaluate the veterinary student learning outcome of 2 methods of equine rectal examination training. STUDY DESIGN: Randomized prospective study. SAMPLE POPULATION: Veterinary students (3rd and 4th year; n = 40) and practicing equine veterinarians (n = 10). METHODS: Year 1: Group 1 (n = 11) and Group 2 students (n = 10) received skilled instructor (SI) and laparoscopic-guidance (LG), respectively, during rectal exam instruction. All students were tested on rectal identification of 4 abdominal organs. Year 2: One group of students (n = 19) was trained and subsequently tested using each technique, first SI, followed by LG. Subjective evaluation of laparoscopy as a teaching tool was achieved with veterinary students and equine practitioners. RESULTS: A significantly greater percentage of students having LG compared to SI were able to correctly identify the left kidney (Year 1) and the spleen, cecum, and right ovary (Year 2). A significantly greater proportion of LG trained students in years 1 and 2 (100% and 95%, respectively) were also able to identify 75% of organs compared with SI (27% and 21%, respectively). Both students and veterinarians uniformly provided favorable feedback for LG in teaching rectal palpation skills. CONCLUSION: The LG method of equine rectal examination instruction resulted in improved learning for identification of several key abdominal organs compared with SI.

Ex vivo evaluation of carpal flexion after partial carpal arthrodesis in horses.

OBJECTIVE: To determine degrees of flexion after arthrodesis of the antebrachiocarpal (ABC) joint, middle carpal (MC), and carpometacarpal (CMC) joints combined (MC/CMC), and carpometacarpal (CMC) joint alone. STUDY DESIGN: Ex vivo study. ANIMALS: Forelimbs (n = 9) from 2- to 10-year-old Quarter Horses (5), Thoroughbred (2), and American Paint Horse (2). METHODS: Using 2 locking compression plates, 3 partial carpal arthrodesis techniques were performed. Cables and deadweights were connected to limbs and each angle of flexion determined 3 times using a protractor and then averaged. Control measurements were obtained before and after arthrodesis, the techniques randomized with Latin square design. Descriptive data were analyzed with Levene's test, Q-Q plots, ANOVA, and Bonferroni test. RESULTS: Mean ± SD carpal flexion results were: controls 150° ± 8°, CMC arthrodesis 149° ± 9°, MC/CMC arthrodesis 43° ± 7.6°, and ABC arthrodesis 25° ± 6.3°. There was no significant reduction in flexion after a CMC arthrodesis compared with controls (P = .21), but there was after ABC (P < .001) and MC/CMC arthrodesis (P < .001), with the ABC arthrodesis significantly reduced compared with an MC/CMC arthrodesis (P < .001). CONCLUSIONS: Whereas CMC arthrodesis does not affect carpal flexion, CMC/MC and ABC arthrodesis markedly reduce the degree of carpal flexion.

Management and long-term outcome of partial glossectomy in 2 horses.

Records were reviewed for 2 horses with partial glossectomy, 1 traumatic and 1 elective. According to long-term follow-up by telephone, both horses had recovered well, experiencing only temporary difficulty while eating, and went on to be ridden successfully using mouth bits. Partial glossectomy, therefore, had a favorable prognosis in 2 performance horses.

Gestion et résultat à long terme de la glossectomie partielle chez 2 chevaux. Les dossiers ont été examinés pour 2 chevaux ayant subi une glossectomie partielle, 1 étant une glossectomie traumatique et 1 étant une glossectomie non urgente. Selon le suivi à long terme par téléphone, les deux chevaux se sont bien rétablis, ont éprouvé seulement une difficulté temporaire à manger et ont ensuite pu être montés avec succès en utilisant des mors. Par conséquent, une glossectomie partielle a présenté un pronostic favorable chez 2 chevaux de performance.(Traduit par Isabelle Vallières).

Evaluation of a minimally invasive arthrodesis technique for the carpometacarpal joint in horses.

OBJECTIVE: To evaluate a minimally invasive technique for arthrodesis of the carpometacarpal (CMC) joint in horses. STUDY DESIGN: Experimental study. ANIMALS: Healthy horses (n=6). METHODS: A 5.5 mm, 3-drill tract arthrodesis technique was evaluated in 1 randomly selected CMC joint in each of 6 normal horses. Peak vertical ground reaction force (GRF) values were recorded before surgery and at 6, 8, and 12 months thereafter. Radiographic and clinical lameness scores were assigned at regular intervals until 12 months after surgery when the horses were euthanatized. Gross and histologic examinations were performed on the treated CMC joints. RESULTS: After surgery, all horses were lame. Clinical resolution of lameness occurred in 2 by 12 months. Mean peak vertical GRF values significantly differed between treated and nontreated limbs at all recorded time points after surgery. Radiographic scores significantly differed from day 0 at all times after surgery, but did not change significantly after 4 months. Intraarticular bony ankylosis only occurred in 2 horses, based on gross, histologic, and microradiographic examination of sagittal sections of the operated CMC joints. CONCLUSION: The 5.5 mm, 3-drill tract arthrodesis technique was considered successful in only 2 of 6 normal CMC joints treated. Greater articular damage may be necessary to achieve arthrodesis in normal horses. Better results may be achieved by technique modification or in horses affected by CMC osteoarthritis.

Comparison of three drilling techniques for carpometacarpal joint arthrodesis in horses.

OBJECTIVE: To evaluate 3 drilling techniques for arthrodesis of the equine carpometacarpal (CMC) joint. STUDY DESIGN: Experimental study. SAMPLE POPULATION: Cadaveric equine forelimbs (n=15). METHODS: Limbs were divided into 3 groups (5 limbs each) to evaluate 3 drilling techniques: (1) use of a 4.5 mm drill bit inserted into the joint through 4 entry points and moved in a fanning motion; (2) a 5.5 mm drill bit inserted through 2 entry points to create 3 nonfanned drill tracts (3 drill technique); and (3) a 4.5 mm drill bit used in a 3 drill technique. The CMC joint was disarticulated after drilling, and cartilage and subchondral bone damage evaluated visually and by gross and microradiographic examination using planimetry. RESULTS: Technique 1 produced significantly more damage of the proximal surface, but significantly less to the subchondral bone of the distal surface. Technique 1 produced the most damage to both the articular cartilage and subchondral bone of the total CMC joint than either of the 3 drill tract techniques; however, the difference between techniques 1 and 2 was not significant. Damage from technique 3 was significantly less than that with techniques 1 or 2. CONCLUSIONS: Techniques 1 and 2 produced the most cartilage and subchondral bone damage with technique 2 changes more equally distributed between proximal and distal joint surfaces. CLINICAL RELEVANCE: Technique 1 (fanning) and 2 (5.5 mm 3 drill tracts) may be preferable to achieve arthrodesis of the CMC joint. Morbidity and efficacy of these arthrodesis techniques need to be evaluated in vivo.

Carpometacarpal osteoarthritis in thirty-three horses.

OBJECTIVE: To describe signalment, clinical, and radiographic changes associated with carpometacarpal osteoarthritis (CMC-OA) and to report long-term outcome. STUDY DESIGN: Case series. ANIMALS: Horses (n=33) with CMC-OA. METHODS: Medical records (1992-2007) of horses diagnosed with CMC-OA were reviewed and signalment, clinical, and radiographic findings retrieved. Owners were contacted for information on the impact of lameness on intended use, response to treatment, progression of lameness, outcome, and owner satisfaction with response to treatment. RESULTS: CMC-OA identified in 39 limbs, occurred predominantly in middle-aged and older Quarter Horses and Arabians, and caused severe lameness that prevented normal use. Characteristic swelling was centered over the 2nd metacarpal bone/2nd carpal bone articulation. Radiographic changes consisted of proliferative new bone, narrowed joint space, and subchondral lysis. Of 20 horses with follow-up, 7 of 14 treated horses were euthanatized within 4 years and 4 of 5 nontreated horses within 3 years. Response to treatment was short lived and considered very poor by most owners. CONCLUSION: CMC-OA seemingly occurs primarily in Quarter Horses and Arabians in our region. Response to conservative treatment is very poor and short-lived with most horses being euthanatized. CLINICAL RELEVANCE: Conventional treatment methods are unsuccessful for treating CMC-OA.

Treatment of carpometacarpal osteoarthritis by arthrodesis in 12 horses.

OBJECTIVE: To evaluate arthrodesis as a treatment for carpometacarpal joint osteoarthritis (CMC-OA). STUDY DESIGN: Case series. ANIMALS: Horses (n=12) with CMC-OA. METHODS: Arthrodesis was facilitated by insertion and fanning of a drill bit into the CMC joint at several (3-5) locations in 15 limbs. Follow-up radiographs were obtained for 7 horses (9 limbs). Outcome was determined by telephone survey of owners based on postoperative pain, return to use, appearance of the limb, and success of treatment. RESULTS: Postoperative pain was slight or moderate in 10 of 12 (83%) horses during the first 30 days, and 11 of 12 (92%) horses were markedly improved by 6 months and capable of returning to work. Radiographically 6 CMC joints had a bony ankylosis at follow-up whereas 3 did not (mean 8.7 months). On long-term follow-up (mean 28.6 months) all horses had reduced severity of lameness, 10 of 12 (83%) were considered "sound," 8 (67%) returned to their original activity, and all owners considered arthrodesis highly successful as a treatment. CONCLUSION: A drilling technique that produced CMC arthrodesis, allowed most horses to return to their original activity and was considered successful by all clients. CLINICAL RELEVANCE: Arthrodesis of the CMC joint should be considered a treatment option for CMC-OA.