Non-invasive electroencephalography in awake cats: Feasibility and application to sensory processing in chronic pain.

BACKGROUND: Feline osteoarthritis (OA) leads to chronic pain and somatosensory sensitisation. In humans, sensory exposure can modulate chronic pain. Recently, electroencephalography (EEG) revealed a specific brain signature to human OA. However, EEG pain characterisation or its modulation does not exist in OA cats, and all EEG were conducted in sedated cats, using intradermal electrodes, which could alter sensory (pain) perception. NEW METHOD: Cats (n=11) affected by OA were assessed using ten gold-plated surface electrodes. Sensory stimuli were presented in random orders: response to mechanical temporal summation, grapefruit scent and mono-chromatic wavelengths (500 nm-blue, 525 nm-green and 627 nm-red light). The recorded EEG was processed to identify event-related potentials (ERP) and to perform spectral analysis (z-score). RESULTS: The procedure was well-tolerated. The ERPs were reported for both mechanical (F3, C3, Cz, P3, Pz) and olfactory stimuli (Cz, Pz). The main limitation was motion artifacts. Spectral analysis revealed a significant interaction between the power of EEG frequency bands and light wavelengths (p<0.001). All wavelengths considered, alpha band proportion was higher than that of delta and gamma bands (p<0.044), while the latter was lower than the beta band (p<0.016). Compared to green and red, exposure to blue light elicited distinct changes in EEG power over time (p<0.001). COMPARISON WITH EXISTING METHOD: This is the first demonstration of EEG feasibility in conscious cats with surface electrodes recording brain activity while exposing them to sensory stimulations. CONCLUSION: The identification of ERPs and spectral patterns opens new avenues for investigating feline chronic pain and its potential modulation through sensory interventions.

Predictive and concurrent validity of pain sensitivity phenotype, neuropeptidomics and neuroepigenetics in the MI-RAT osteoarthritic surgical model in rats.

Background: Micro-RNAs could provide great insights about the neuropathological mechanisms associated with osteoarthritis (OA) pain processing. Using the validated Montreal Induction of Rat Arthritis Testing (MI-RAT) model, this study aimed to characterize neuroepigenetic markers susceptible to correlate with innovative pain functional phenotype and targeted neuropeptide alterations. Methods: Functional biomechanical, somatosensory sensitization (peripheral-via tactile paw withdrawal threshold; central-via response to mechanical temporal summation), and diffuse noxious inhibitory control (via conditioned pain modulation) alterations were assessed sequentially in OA (n = 12) and Naïve (n = 12) rats. Joint structural, targeted spinal neuropeptides and differential expression of spinal cord micro-RNAs analyses were conducted at the sacrifice (day (D) 56). Results: The MI-RAT model caused important structural damages (reaching 35.77% of cartilage surface) compared to the Naïve group (P < 0.001). This was concomitantly associated with nociceptive sensitization: ipsilateral weight shift to the contralateral hind limb (asymmetry index) from -55.61% ± 8.50% (D7) to -26.29% ± 8.50% (D35) (P < 0.0001); mechanical pain hypersensitivity was present as soon as D7 and persisting until D56 (P < 0.008); central sensitization was evident at D21 (P = 0.038); pain endogenous inhibitory control was distinguished with higher conditioned pain modulation rate (P < 0.05) at D7, D21, and D35 as a reflect of filtrated pain perception. Somatosensory profile alterations of OA rats were translated in a persistent elevation of pro-nociceptive neuropeptides substance P and bradykinin, along with an increased expression of spinal miR-181b (P = 0.029) at D56. Conclusion: The MI-RAT OA model is associated, not only with structural lesions and static weight-bearing alterations, but also with a somatosensory profile that encompasses pain centralized sensitization, associated to active endogenous inhibitory/facilitatory controls, and corresponding neuropeptidomic and neuroepigenetic alterations. This preliminary neuroepigenetic research confirms the crucial role of pain endogenous inhibitory control in the development of OA chronic pain (not only hypersensitivity) and validates the MI-RAT model for its study.

Effect of Pulp Chamber Access, Instrumentation, Obturation, and Restoration on the Fracture Resistance of Endodontically Treated Canine Teeth in Dogs.

Veterinary studies documenting the effect of endodontic treatment on tooth fracture resistance are scarce. The objective of this ex vivo study was to evaluate the effects of mesial access preparation and restoration, as well as pulp chamber access, instrumentation, obturation, and restoration, on the fracture resistance and characteristics of canine teeth in dogs. Sixty-five dog canine teeth were divided into 4 groups: 1. Standard endodontic treatment through a mesial access only; 2. Treatment as per group 1, adding an incisal access, instrumentation and obturation of the pulp chamber, and restoration of the access; 3. Treatment as per group 2, without pulp chamber obturation or restoration of the incisal access; and 4. Untreated teeth. The fracture resistance and characteristics of each group were documented using axial compression testing, angled 45° disto-occlusal to the long axis of the crown. The maximum force prior to fracture in groups 1, 3, and 4 were not statistically different, demonstrating that restored mesial and incisal accesses with pulp chamber instrumentation did not statistically affect fracture resistance. However, obturated and restored group 2 teeth demonstrated decreased fracture resistance compared to all other groups (P < .001). Additionally, 26.7% of group 1 teeth sustained complicated crown fractures, while 100% of group 2 teeth fractured within the obturation or restorative materials, preventing pulp exposure in these cases. Although the cause and clinical importance of decreased tooth fracture resistance following pulp chamber obturation and restoration remains unknown, it may provide protective value for maintaining a coronal seal in the event of tooth fracture.

Face and Predictive Validity of MI-RAT (Montreal Induction of Rat Arthritis Testing), a Surgical Model of Osteoarthritis Pain in Rodents Combined with Calibrated Exercise.

Validating animal pain models is crucial to enhancing translational research and response to pharmacological treatment. This study investigated the effects of a calibrated slight exercise protocol alone or combined with multimodal analgesia on sensory sensitivity, neuroproteomics, and joint structural components in the MI-RAT model. Joint instability was induced surgically on day (D) 0 in female rats (N = 48) distributed into sedentary-placebo, exercise-placebo, sedentary-positive analgesic (PA), and exercise-PA groups. Daily analgesic treatment (D3-D56) included pregabalin and carprofen. Quantitative sensory testing was achieved temporally (D-1, D7, D21, D56), while cartilage alteration (modified Mankin's score (mMs)) and targeted spinal pain neuropeptide were quantified upon sacrifice. Compared with the sedentary-placebo (presenting allodynia from D7), the exercise-placebo group showed an increase in sensitivity threshold (p < 0.04 on D7, D21, and D56). PA treatment was efficient on D56 (p = 0.001) and presented a synergic anti-allodynic effect with exercise from D21 to D56 (p < 0.0001). Histological assessment demonstrated a detrimental influence of exercise (mMs = 33.3%) compared with sedentary counterparts (mMs = 12.0%; p < 0.001), with more mature transformations. Spinal neuropeptide concentration was correlated with sensory sensitization and modulation sites (inflammation and endogenous inhibitory control) of the forced mobility effect. The surgical MI-RAT OA model coupled with calibrated slight exercise demonstrated face and predictive validity, an assurance of higher clinical translatability.

Muscular morphometric study of the canine shoulder for the design of 3D-printed endoprostheses in dogs with osteosarcoma of the proximal humerus: a pilot cadaveric study by MRI.

OBJECTIVE: Osteosarcoma frequently affects the proximal humerus in dogs. In veterinary medicine, no therapeutic option for the treatment of osteosarcoma satisfactorily preserves limb function. 3D-printed personalized endoprosthesis offers a promising treatment option. Morphometric data, necessary for the design of the endoprosthesis, are currently lacking in canine patients. Our objective was to acquire the morphometric data necessary to refine the design of the endoprosthesis. ANIMAL: A single canine cadaveric thoracic limb. PROCEDURES: Sagittal proton-density, and sagittal, dorsal, and transverse T1-weighted sequences of the thoracic limb were acquired with a 1.5 Tesla Magnetic Resonance Imaging (MRI) unit. Nineteen muscles of interest were subsequently identified using medical imaging software (Mimics©) and their volume was reconstructed in 3D using computer-aided design (CATIA©). Mormophetric data were recorded for each of the 19 muscles. The same canine cadaver was then dissected to measure the same parameters. RESULTS: All muscles were successfully identified with data consistent with the dissected cadaveric data. Certain muscles were more challenging to isolate on MRI, namely the heads of the triceps brachii, superficial pectoral, and latissimus dorsi. The relative distribution of muscle volumes was similar to historical data. Muscle tissue density was not significantly affected by freezing (1.059 g/cm3). CLINICAL RELEVANCE: MRI is a useful tool to collect morphometric data but imperfect if used alone. This approach was the first attempt to validate more general morphometric data that could be used to refine the design of custom 3D-printed prostheses for limb-sparing of the proximal humerus. Further imaging studies are warranted to refine our model.

Development of Two Innovative Performance-Based Objective Measures in Feline Osteoarthritis: Their Reliability and Responsiveness to Firocoxib Analgesic Treatment.

The metrological properties of two performance-based outcome measures of feline osteoarthritis (OA), namely Effort Path (Path) and Stairs Assay Compliance (Stairs), were tested. Cats naturally affected by OA (n = 32) were randomly distributed into four groups (A: 0.40, B: 0.25, C: 0.15, or D: 0.00 mg firocoxib/kg bodyweight) and assessed during baseline, treatment, and recovery periods. For Path, from an elevated walking platform, the cats landed on a pressure-sensitive mattress and jumped up onto a second elevated platform. Analysis included velocity, time to completion, peak vertical force (PVF), and vertical impulse. For Stairs, the number of steps and time to completion were recorded for 16 steps up and down in a 4 min period. Reliability was moderate to very good for Path and poor to good for Stairs. Different normalization methods are described in the manuscript. The placebo group remained stable within-time in Path, whereas treated cats trotted faster on the ramp (p < 0.0001), improved their PVF (p < 0.018) and completed the task quicker (p = 0.003). The percentage of cats completing the Stairs finish line was higher under treatment (p < 0.036), with huge effect size, the placebo group results being stable within-time. Both are promising performance-based outcome measures to better diagnose and manage feline OA pain.

A 2022 Systematic Review and Meta-Analysis of Enriched Therapeutic Diets and Nutraceuticals in Canine and Feline Osteoarthritis.

With osteoarthritis being the most common degenerative disease in pet animals, a very broad panel of natural health products is available on the market for its management. The aim of this systematic review and meta-analysis, registered on PROSPERO (CRD42021279368), was to test for the evidence of clinical analgesia efficacy of fortified foods and nutraceuticals administered in dogs and cats affected by osteoarthritis. In four electronic bibliographic databases, 1578 publications were retrieved plus 20 additional publications from internal sources. Fifty-seven articles were included, comprising 72 trials divided into nine different categories of natural health compound. The efficacy assessment, associated to the level of quality of each trial, presented an evident clinical analgesic efficacy for omega-3-enriched diets, omega-3 supplements and cannabidiol (to a lesser degree). Our analyses showed a weak efficacy of collagen and a very marked non-effect of chondroitin-glucosamine nutraceuticals, which leads us to recommend that the latter products should no longer be recommended for pain management in canine and feline osteoarthritis.

Estrogenic impregnation alters pain expression: analysis through functional neuropeptidomics in a surgical rat model of osteoarthritis.

PURPOSE: Several observational studies suggest that estrogens could bias pain perception. To evaluate the influence of estrogenic impregnation on pain expression, a prospective, randomized, controlled, blinded study was conducted in a Sprague-Dawley rat model of surgically induced osteoarthritis (OA). METHODS: Female rats were ovariectomized and pre-emptive 17ß-estradiol (0.025 mg, 90-day release time) or placebo pellets were installed subcutaneously during the OVX procedures. Thirty-five days after, OA was surgically induced on both 17ß-estradiol (OA-E) and placebo (OA-P) groups. Mechanical hypersensitivity was assessed by static weight-bearing (SWB) and paw withdrawal threshold (PWT) tests. Mass spectrometry coupled with high-performance liquid chromatography (HPLC-MS) was performed to quantify the spinal pronociceptive neuropeptides substance P (SP), calcitonin gene-related peptide (CGRP), bradykinin (BK), somatostatin (SST), and dynorphin-A (Dyn-A). RESULTS: Compared to control, ovariectomized rats presented higher SP (P = 0.009) and CGRP (P = 0.017) concentrations. OA induction increased the spinal level of SP (+ 33%, P < 0.020) and decreased the release of BK (- 20%, (P < 0.037)). The OA-E rats at functional assessment put more % body weight on the affected hind limb than OA-P rats at D7 (P = 0.027) and D56 (P = 0.033), and showed higher PWT at D56 (P = 0.009), suggesting an analgesic and anti-allodynic effect of 17ß-estradiol. Interestingly, the 17ß-estradiol treatment counteracted the increase of spinal concentration of Dyn-A (P < 0.016) and CGRP (P < 0.018). CONCLUSION: These results clearly indicate that 17ß-estradiol interfers with the development of central sensitization and confirm that gender dimorphism should be considered when looking at pain evaluation.

Personalized endoprostheses for the proximal humerus and scapulohumeral joint in dogs: Biomechanical study of the muscles' contributions during locomotion.

Osteosarcoma represents one of the most common bone tumours in dogs. It commonly occurs in the proximal humerus, the most affected anatomic site. Until recently, amputation or limb-sparing surgery leading to an arthrodesis coupled with chemotherapy were the only available treatments, but they often lead to complications, reduced mobility and highly impact dog's quality of life. Prototypes of both articulated and monobloc (no mobility) patient-specific endoprostheses have been designed to spare the limb afflicted with osteosarcoma of the proximal humerus. This study focuses on the biomechanical effects of endoprostheses and shoulder muscle kinematics. For each of the endoprosthesis designs, a minimal number of muscles needed to ensure stability and a certain degree of joint movement during walking is sought. A quasi-static study based on an optimization method, the minimization of the sum of maximal muscle stresses, was carried out to assess the contribution of each muscle to the shoulder function. The identification of the most important muscles and their impact on the kinematics of the prosthetic joint lead to an improvement of the endoprosthesis design relevance and implantation feasibility.

Three-dimensional kinematic evaluation of lateral suture stabilization in an in vitro canine cranial cruciate deficient stifle model.

The impact of surgical correction of cranial cruciate ligament rupture (CCLR) on 3D kinematics has not been thoroughly evaluated in dogs. The success of current techniques remains limited, as illustrated by suboptimal weightbearing and progression of osteoarthritis. The inability to restore the stifle's 3D kinematics might be a key element in understanding these suboptimal outcomes. The objective of this study was to evaluate the impact of lateral suture stabilization (LSS) on the 3D kinematics of the canine stifle joint. We hypothesized that LSS would not restore 3D kinematics in our model. Ten cadaveric pelvic limbs collected from large dogs (25-40 kg) were tested using a previously validated apparatus that simulates gait. Three experimental conditions were compared: (a) intact stifle; (b) unstable stifle following cranial cruciate ligament transection (CCLt) and (c) CCLt stabilized by LSS. Three-dimensional kinematics were collected through 5 loading cycles simulating the stance phase of gait and curves were analyzed using a Wilcoxon signed-rank test. LSS restored baseline kinematics for the entire stance phase for cranial and lateromedial translation, flexion, and abduction. It restored distraction over 90% of the stance phase. Internal rotation was limited, but not restored. This in vitro study had limitations, as it used a simplified model of stifle motion and weight-bearing. The results of this study report that LSS can restore physiologic 3D kinematics largely comparable to those of healthy stifles. Suboptimal outcome in patients following CCLR stabilization by LSS may therefore result from causes other than immediate postoperative abnormal 3D kinematics.

L-PGDS deficiency accelerated the development of naturally occurring age-related osteoarthritis.

Osteoarthritis (OA) is the most common musculoskeletal disorder among the elderly. It is characterized by progressive cartilage degradation, synovial inflammation, subchondral bone remodeling and pain. Lipocalin prostaglandin D synthase (L-PGDS) is responsible for the biosynthesis of PGD2, which has been implicated in the regulation of inflammation and cartilage biology. This study aimed to evaluate the effect of L-PGDS deficiency on the development of naturally occurring age-related OA in mice. OA-like structural changes were assessed by histology, immunohistochemistry, and micro-computed tomography. Pain related behaviours were assessed using the von Frey and the open-field assays. L-PGDS deletion promoted cartilage degradation during aging, which was associated with enhanced expression of extracellular matrix degrading enzymes, matrix metalloprotease 13 (MMP-13) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), and their breakdown products, C1,2C, VDIPEN and NITEG. Moreover, L-PGDS deletion enhanced subchondral bone changes, but had no effect on its angiogenesis. Additionally, L-PGDS deletion increased mechanical sensitivity and reduced spontaneous locomotor activity. Finally, we showed that the expression of L-PGDS was elevated in aged mice. Together, these findings indicate an important role for L-PGDS in naturally occurring age-related OA. They also suggest that L-PGDS may constitute a new efficient therapeutic target in OA.

Role of Lipocalin-Type Prostaglandin D Synthase in Experimental Osteoarthritis.

OBJECTIVE: Lipocalin-type prostaglandin D synthase (L-PGDS) catalyzes the formation of prostaglandin D2 (PGD2 ), which has important roles in inflammation and cartilage metabolism. We undertook this study to investigate the role of L-PGDS in the pathogenesis of osteoarthritis (OA) using an experimental mouse model. METHODS: Experimental OA was induced in wild-type (WT) and L-PGDS-deficient (L-PGDS-/- ) mice (n = 10 per genotype) by destabilization of the medial meniscus (DMM). Cartilage degradation was evaluated by histology. The expression of matrix metalloproteinase 13 (MMP-13) and ADAMTS-5 was assessed by immunohistochemistry. Bone changes were determined by micro-computed tomography. Cartilage explants from L-PGDS-/- and WT mice (n = 6 per genotype) were treated with interleukin-1α (IL-1α) ex vivo in order to evaluate proteoglycan degradation. Moreover, the effect of intraarticular injection of a recombinant adeno-associated virus type 2/5 (rAAV2/5) encoding L-PGDS on OA progression was evaluated in WT mice (n = 9 per group). RESULTS: Compared to WT mice, L-PGDS-/- mice had exacerbated cartilage degradation and enhanced expression of MMP-13 and ADAMTS-5 (P < 0.05). Furthermore, L-PGDS-/- mice displayed increased synovitis and subchondral bone changes (P < 0.05). Cartilage explants from L-PGDS-/- mice showed enhanced proteoglycan degradation following treatment with IL-1α (P < 0.05). Intraarticular injection of rAAV2/5 encoding L-PGDS attenuated the severity of DMM-induced OA-like changes in WT mice (P < 0.05). The L-PGDS level was increased in OA tissues of WT mice (P < 0.05). CONCLUSION: Collectively, these findings suggest a protective role of L-PGDS in OA, and therefore enhancing levels of L-PGDS may constitute a promising therapeutic strategy.

Limb-sparing in dogs using patient-specific, three-dimensional-printed endoprosthesis for distal radial osteosarcoma: A pilot study.

Limb-sparing for distal radial osteosarcoma has a high rate of complications. Using personalized three-dimensional (3D)-printed implants might improve outcome. The goals of this study were to optimize use of patient-specific, 3D-printed endoprostheses for limb-sparing in dogs in the clinical environment and to report the outcome. This was a pilot study where five client-owned dogs were enrolled. Computed tomography (CT) of the thoracic limbs was performed, which was used to create patient-specific endoprostheses and cutting guides, and repeated on the day of surgery. Intra-arterial (IA) carboplatin was introduced in the clinical management. Limb-sparing was performed. Outcome measures were time required to produce the endoprosthesis and cutting guide, fit between cutting guide and endoprosthesis with host bones, gait analysis, size of the tumour, percent tumour necrosis, complications, disease-free interval (DFI) and survival time (ST). Four dogs received IA carboplatin. Excessive tumour growth between planning CT and surgery did not occur in any dog. The interval between the CT and surgery ranged from 14 to 70 days. Fit between the cutting-guide and endoprosthesis with the host bones was good to excellent. At least one complication occurred in all dogs. Two dogs were euthanized with STs of 192 and 531 days. The other dogs were alive with a follow up of 534 to 575 days. IA chemotherapy is a promising strategy to minimize the risk of excessive tumour growth while waiting for the endoprosthesis and cutting-guide to be made. The design of the cutting-guide was critical for best fit of the endoprosthesis with host bones.

Three-dimensional kinematic evaluation of Tightrope CCL in a canine in vitro cranial cruciate deficient stifle model.

The impact of surgical correction of cranial cruciate ligament-deficient stifles (CCDS) on the 3-dimensional (3D) kinematics of the canine stifle has been sparsely evaluated. Tightrope (TR) cranial cruciate ligament (CCL) has been proposed to restore baseline 3D kinematics in CCDS by using isometric points. We hypothesized that TR would restore baseline 3D kinematics of the stifle in our model. Ten pelvic limbs were used with a previously validated apparatus. Three experimental conditions were evaluated: i) intact stifle, ii) cranial cruciate ligament transection (CCLt), and iii) CCLt stabilized with TR; kinematic data was recorded. Tightrope CCL in CCDS did not limit sagittal flexion. Tightrope CCL neutralized internal rotation without restoring baseline curves, but it did not restore abduction, nor did it neutralize or restore cranial translation, but it did restore latero-medial and proximo-distal translations. In our model, TR without pre-conditioning of the FiberTape strands did not restore baseline stifle 3D kinematics and residual cranial translation could result in frequent meniscal tears.

L'impact de la correction chirurgicale d'une déficience du ligament croisé crânial du genou (CCDS) sur la cinématique du grasset canin a été peu étudié. La technique de restauration du ligament croisé crânial (CCL) appelée 'Tightrope' (TR) a été proposée pour restaurer la cinématique 3D lors de CCDS en utilisant des points isométriques. Nous avons émis l'hypothèse que la technique TR restaurerait la cinématique 3D d'origine du grasset dans notre modèle. Dix membres pelviens ont été utilisés avec un appareil préalablement validé. Trois conditions expérimentales furent évaluées : i) grasset intact, ii) transsection du ligament croisé crânial (CCLt), et iii) CCLt stabilisé par TR; et les données de cinématique furent enregistrées. La technique TR lors de CCL n'a pas limité la flexion sagittale. Cette technique neutralisait la rotation interne sans restaurer les courbes d'origine, mais elle ne restaurait pas l'abduction, ni ne neutralisait ou restaurait une translation crâniale, mais elle a restauré les translations latéro-médiale et proximo-distale. Dans notre modèle, la technique TR sans préconditionnement des bandes FiberTape n'a pas restauré la cinématique 3D d'origine et une translation crâniale résiduelle pourrait résulter en des déchirures fréquentes du ménisque.(Traduit par Docteur Serge Messier).

Personalized 3D-printed endoprostheses for limb sparing in dogs: Modeling and in vitro testing.

Osteosarcoma is the most common type of bone cancer in dogs, treatable by amputation or limb-sparing surgery. For the latter, commercially available plate - endoprosthesis assemblies require contouring, to be adapted to the patient's bone geometry, and lead to sub-optimal results. The use of additively-manufactured personalized endoprostheses and cutting guides for distal radius limb-sparing surgery in dogs presents a promising alternative. Specialized software is used for the bone structure reconstruction from the patient's CT scans and for the design of endoprostheses and cutting guides. The prostheses are manufactured from a titanium alloy using a laser powder bed fusion system, while the cutting guides are manufactured from an ABS plastic using a fused deposition modeling system. A finite element model of an instrumented limb was developed and validated using experimental testing of a cadaveric limb implanted with a personalized endoprosthesis. Personalized endoprostheses and cutting guides can reduce limb sparing surgery time by 25-50% and may reduce the risk of implant failure. The numerical model was validated using the kinematics and force-displacement diagrams of the implant-limb construct. The model indicated that a modulus of elasticity of an implant material ranging from 25 to 50 GPa would improve the stress distribution within the implant. The results of the current study will allow optimization of the design of the personal implants in both veterinary and human patients.

Osteoarthritic pain model influences functional outcomes and spinal neuropeptidomics: A pilot study in female rats.

Osteoarthritis, the leading cause of chronic joint pain, is studied through different animal models, but none of them is ideal in terms of reliability and translational value. In this pilot study of female rats, 3 surgical models of osteoarthritic pain, i.e., destabilization of the medial meniscus (DMM), cranial cruciate ligament transection (CCLT), and the combination of both surgical models (COMBO) and 1 chemical model [intra-articular injection of monosodium iodoacetate (MIA)] were compared for their impact on functional pain outcomes [static weight-bearing (SWB) and punctate tactile paw withdrawal threshold (PWT)] and spinal neuropeptides [substance P (SP), calcitonin gene-related peptide (CGRP), bradykinin (BK), and somatostatin (SST)]. Six rats were assigned to each model group and a sham group. Both the chemical model (MIA) and surgical COMBO model induced functional alterations in SWB and PWT, with the changes being more persistent in the surgical combination group. Both models also produced an increase in levels of pro-nociceptive and anti-nociceptive neuropeptides at different timepoints. Pain comparison with the MIA model showed the advantage of a surgical model, especially the combination of the DMM and CCLT models, whereas each surgical model alone only led to temporary functional alterations and no change in neuropeptidomics.

L'arthrose, la principale cause de douleur chronique articulaire, est étudiée à travers différents modèles animaux, mais aucun d'eux n'est idéal en termes de fiabilité et de valeur translationnelle. Trois modèles chirurgicaux de douleur arthrosique, c'est-à-dire, la déstabilisation du ménisque médial, la transsection du ligament croisé crânial et la combinaison des deux, ainsi qu'un modèle chimique (injection intraarticulaire de mono-iodoacétate de sodium) ont été comparés dans cette étude pilote chez des rattes quant à leurs impacts sur les évaluations fonctionnelles de la douleur (distribution pondérale statique, évaluation ponctuelle de l'allodynie tactile) et les neuropeptides spinaux (substance P, peptide relié au gène de la calcitonine, bradykinine et somatostatine). Six rats ont été assignés à chacun des modèles et un groupe Sham. Autant le modèle du mono-iodoacétate de sodium que celui de la combinaison chirurgicale ont tous les deux induits des altérations fonctionnelles de la distribution pondérale statique et du seuil de retrait de la patte suite à une stimulation ponctuelle tactile, mais avec des changements plus persistants dans le groupe de la combinaison chirurgicale. Ces deux modèles ont également engendré une augmentation des niveaux en neuropeptides pro-nociceptifs et anti-nociceptifs à différents moments. Un intérêt du modèle chirurgical a été démontré suite à la comparaison de la douleur avec le modèle du mono-iodoacétate de sodium, en particulier la déstabilisation du ménisque médial combinée à la transsection du ligament croisé crânial, tandis que les inductions chirurgicales unique entraînaient des altérations fonctionnelles temporaires avec aucun changement neuropeptidomique.(Traduit par les auteurs).

Inflammation and Hypervascularization in a Large Animal Model of Knee Osteoarthritis: Imaging with Pathohistologic Correlation.

PURPOSE: To evaluate if synovial inflammation and hypervascularization are present in a dog model of knee osteoarthritis and can be detected on conventional magnetic resonance imaging (MRI), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), contrast-enhanced magnetic resonance imaging (CE-MRI), and quantitative digital subtraction angiography (Q-DSA) imaging. MATERIALS AND METHODS: Six dogs underwent MRI and angiography of both knees before and 12 weeks after right knee anterior cruciate ligament injury. Synovial vascularity was evaluated on CE-MRI, DCE-MRI, and Q-DSA by 2 independent observers. Synovial inflammation and vascularity were histologically scored independently. Cartilage lesions and osteophytes were analyzed macroscopically, and cartilage volumetry was analyzed by MRI. Vascularity and osteoarthritis markers on imaging were compared before and after osteoarthritis generation, and between the osteoarthritis model and the control knee, using linear mixed models accounting for within-dog correlation. RESULTS: In all knees, baseline imaging showed no abnormalities. Control knees did not develop significant osteoarthritis changes, synovial inflammation, or hypervascularization. In osteoarthritis knees, mean synovial enhancement score on CE-MR imaging increased by 13.1 ± 0.59 (P < .0001); mean synovial inflammation variable increased from 47.33 ± 18.61 to 407.97 ± 18.61 on DCE-MR imaging (P < .0001); and area under the curve on Q-DSA increased by 1058.58 ± 199.08 (P = .0043). Synovial inflammation, hypervascularization, and osteophyte formations were present in all osteoarthritis knees. Histology scores showed strong correlation with CE-MR imaging findings (Spearman correlation coefficient [SCC] = 0.742; P = .0002) and Q-DSA findings (SCC = 0.763; P < .0001) and weak correlation with DCE-MR imaging (SCC = -0.345; P = .329). Moderate correlation was found between CE-MR imaging and DSA findings (SCC = 0.536; P = .0004). CONCLUSIONS: In this early-stage knee osteoarthritis dog model, synovial inflammation and hypervascularization were found on imaging and confirmed by histology.

Pain characterization and response to palliative care in dogs with naturally-occurring appendicular osteosarcoma: An open label clinical trial.

This study aimed to characterize bone cancer pain (quantitative sensory testing (QST), stance asymmetry index, actimetry, scores of pain and quality of life (QoL)) in dogs with appendicular osteosarcoma (OSA), and to evaluate a stepwise palliative analgesic treatment. The pain profile of thirteen client-owned dogs with OSA was compared with seven healthy dogs. Dogs with OSA were then enrolled in a prospective, open-label, clinical trial. Outcome measures included: primary and secondary mechanical thresholds (MT), conditioned pain modulation (CPM), stance asymmetry index, actimetry (most and least active periods), visual analog scales and QoL. After baseline assessments, stepwise treatment comprised orally administered cimicoxib (2 mg/kg q 24h), amitriptyline (1-1.5 mg/kg q 24h) and gabapentin (10 mg/kg q 8h); re-evaluations were performed after 14 (D14), 21 (D21) and 28 (D28) days, respectively. Statistics used mixed linear models (α = 5%; one-sided). Centralized nociceptive sensitivity (primary and secondary MT, and dynamic allodynia) was recorded in OSA dogs. Healthy dogs had responsive CPM, but CPM was deficient in OSA dogs. Construct validity was observed for the QST protocol. Asymmetry index was significantly present in OSA dogs. The CPM improved significantly at D14. When compared with baseline (log mean ± SD: 4.1 ± 0.04), most active actimetry significantly improved at D14 (4.3 ± 0.04), D21 and D28 (4.2 ± 0.04 for both). When compared with baseline, least active actimetry significantly decreased after treatment at all time-points indicating improvement in night-time restlessness. No other significant treatment effect was observed. Except for tactile threshold and actimetry, all outcomes worsened when gabapentin was added to cimicoxib-amitriptyline. Dogs with bone cancer are affected by widespread somatosensory sensitivity characterized by peripheral and central sensitization and have a deficient inhibitory system. This severe pain is mostly refractory to palliative analgesic treatment, and the latter was only detected by specific and sensitive outcomes.

High in vivo levels of adipsin lead to increased knee tissue degradation in osteoarthritis: data from humans and animal models.

Objective: This study explored the role of the adipokine adipsin in OA. Methods: Control and OA articular tissues, cells and serum were obtained from human individuals. Serum adipsin levels of human OA individuals were compared with cartilage volume loss as assessed by MRI at 48 months. Human adipsin expression was determined by PCR, its production in tissues by immunohistochemistry, and in SF and serum by a specific assay. OA was surgically induced in wild-type (Df+/+) and adipsin-deficient (Df-/-) mice, and synovial membrane and cartilage processed for histology and immunohistochemistry. Results: Adipsin levels were significantly increased in human OA serum, SF, synovial membrane and cartilage compared with controls, but the expression was similar in chondrocytes, synoviocytes and osteoblasts. Multivariate analysis demonstrated that human serum adipsin levels were significantly associated (P = 0.045) with cartilage volume loss in the lateral compartment of the knee. Destabilization of the medial meniscus-Df-/- mice showed a preservation of the OA synovial membrane and cartilage lesions (P ⩽ 0.026), the latter corroborated by the decreased production of cartilage degradation products and proteases (P ⩽ 0.047). The adipsin effect is likely due to a deficient alternative complement pathway (P ⩽ 0.036). Conclusion: In human OA, higher serum adipsin levels were associated with greater cartilage volume loss in the lateral compartment, and adipsin deficiency led to a preservation of knee structure. Importantly, we documented an association between adipsin and OA synovial membrane and cartilage degeneration through the activation of the complement pathway. This study highlights the clinical relevance of adipsin as a valuable biomarker and potential therapeutic target for OA.