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.

Pegbelfermin, a PEGylated FGF21 analogue, has pharmacology without bone toxicity after 1-year dosing in skeletally-mature monkeys.

Pegbelfermin (PGBF) is a PEGylated fibroblast growth factor 21 (FGF21) analogue in development for treatment of nonalcoholic steatohepatitis (NASH). Mouse models highlight potential utility of FGF21 in NASH, but also suggest negative effects on bone, though these findings are confounded by profound FGF21-related decreases in body mass/growth. This study aimed to profile PGBF-related bone effects in adult nonhuman primates after long-term, clinically-relevant exposures. Adult male cynomolgus monkeys received weekly subcutaneous PGBF (0.3, 0.75 mg/kg) or control injections for 1 year (n = 5/group). Assessments included body weight, clinical chemistry, adiponectin levels, bone turnover biomarkers, skeletal radiography, pharmacokinetics, immunogenicity, and histopathology. Bone densitometry and body composition were evaluated in vivo and/or ex vivo with dual-energy x-ray absorptiometry, peripheral quantitative computed tomography, and biomechanical strength testing. After 1 year of PGBF administration, there was clear evidence of sustained PGBF pharmacology in monkeys (peak increase in serum adiponectin of 1.7× and 2.35× pretest at 0.3 and 0.75 mg/kg PGBF, respectively) and decreased body weight compared with control at exposures comparable to those tested in humans. At 0.75 mg/kg PGBF, pharmacologically-mediated reductions in lean mass, lean area, and fat area were observed relative to controls. There were no PGBF-related effects on bone biomarkers, radiography, densitometry, or strength. Together, these data demonstrate that PGBF did not adversely alter bone metabolism, density, or strength following 1 year of dosing at clinically relevant (0.7-2.2× human AUC[0-168 h] at 20 mg once weekly), pharmacologically-active exposures in adult monkeys, suggesting a low potential for negative effects on bone quality in adult humans.

Nonclinical cardiovascular safety evaluation of romosozumab, an inhibitor of sclerostin for the treatment of osteoporosis in postmenopausal women at high risk of fracture.

Romosozumab (EVENITY™ [romosozumab-aqqg in the US]) is a humanized monoclonal antibody that inhibits sclerostin and has been approved in several countries for the treatment of osteoporosis in postmenopausal women at high risk of fracture. Sclerostin is expressed in bone and aortic vascular smooth muscle (AVSM). Its function in AVSM is unclear but it has been proposed to inhibit vascular calcification, atheroprogression, and inflammation. An increased incidence of positively adjudicated serious cardiovascular adverse events driven by an increase in myocardial infarction and stroke was observed in romosozumab-treated subjects in a clinical trial comparing alendronate with romosozumab (ARCH; NCT01631214) but not in a placebo-controlled trial (FRAME; NCT01575834). To investigate the effects of sclerostin inhibition with sclerostin antibody on the cardiovascular system, a comprehensive nonclinical toxicology package with additional cardiovascular studies was conducted. Although pharmacodynamic effects were observed in the bone, there were no functional, morphological, or transcriptional effects on the cardiovascular system in animal models in the presence or absence of atherosclerosis. These nonclinical studies did not identify evidence that proves the association between sclerostin inhibition and adverse cardiovascular function, increased cardiovascular calcification, and atheroprogression.

Sensitivity of functional targeted neuropeptide evaluation in testing pregabalin analgesic efficacy in a rat model of osteoarthritis pain.

The monosodium iodoacetate (MIA)-induced joint degeneration in rats is the most used animal model to screen analgesic drugs to alleviate osteoarthritis (OA) pain. This study aimed to evaluate the analgesic efficacy of pregabalin (PGB) in an MIA-induced OA model in rodents by using functional and neuroproteomic pain assessment methods. Treatment group included PGB in curative intent over 9 days compared to gold standard therapy (positive controls) and placebo (negative control). Functional assessments of pain (quantitative sensory testing and operant test) were performed concomitantly with spinal neuropeptides quantification. At day 21 post-OA induction, PGB in MIA rats reduced tactile allodynia (P = 0.028) and improved the place escape/avoidance behaviour (P = 0.04) compared to values recorded at last time-point before initiating analgesic therapy. All spinal neuropeptide concentrations, such as substance P, calcitonin gene-related peptide, bradykinin and somatostatin, came back to normal (non-affected) rat values, compared to their increase observed in MIA rats receiving the placebo (P < 0.0001). Initiated 13 days after chemical OA induction, repeated medication with PGB provided analgesia according to quantitative sensory testing, operant test and targeted neuropeptides pain assessment methods. This report highlights the interest of using reliable and sensitive methods like targeted neuropeptide quantification to detect the analgesic effects of a test article with concomitant functional assessments of pain when studying OA pain components.

Computational fluid dynamics simulations as a complementary study for transcatheter endovascular stent implantation for re-coarctation of the aorta associated with minimal pressure drop: an aneurysmal ductal ampulla with aortic isthmus narrowing.

BACKGROUND: Transcatheter stent implantation has been employed to treat re-coarctation of the aorta in adolescents and young adults. The aim of this work is to use computational fluid dynamics to characterise haemodynamics associated with re-coarctation involving an aneurysmal ductal ampulla and aortic isthmus narrowing, which created minimal pressure drop, and to incorporate computational fluid dynamics's findings into decision-making concerning catheter-directed treatment. METHODS: Computational fluid dynamics permits numerically solving the Navier-Stokes equations governing pulsatile flow in the aorta, based on patient-specific data. We determined flow-velocity fields, wall shear stresses, oscillatory shear indices, and particle stream traces, which cannot be ascertained from catheterisation data or magnetic resonance imaging. RESULTS: Computational fluid dynamics showed that, as flow entered the isthmus, it separated from the aortic wall, and created vortices leading to re-circulating low-velocity flow that induced low and multidirectional wall shear stress, which could sustain platelet-mediated thrombus formation in the ampulla. In contrast, as flow exited the isthmus, it created a jet leading to high-velocity flow that induced high and unidirectional wall shear stress, which could eventually undermine the wall of the descending aorta. SUMMARY: We used computational fluid dynamics to study re-coarctation involving an aneurysmal ductal ampulla and aortic isthmus narrowing. Despite minimal pressure drop, computational fluid dynamics identified flow patterns that would place the patient at risk for: thromboembolic events, rupture of the ampulla, and impaired descending aortic wall integrity. Thus, catheter-directed stenting was undertaken and proved successful. Computational fluid dynamics yielded important information, not only about the case presented, but about the complementary role it can serve in the management of patients with complex aortic arch obstruction.

Comparison of lidocaine and lidocaine-epinephrine for the paravertebral brachial plexus block in dogs.

OBJECTIVE: To compare the motor and sensory block efficacy and duration of a modified paravertebral brachial plexus block (PBPB) after administration of lidocaine alone (LI) or combined with epinephrine (LE). STUDY DESIGN: Prospective, randomized, blinded, crossover study. ANIMALS: A total of eight healthy female Beagle dogs. METHODS: Under general anesthesia, modified PBPB was performed on the left thoracic limb using neurostimulation and/or ultrasound guidance to administer lidocaine (2 mg kg-1; 0.2 mL kg-1) either alone (treatment LI, n = 10) or with epinephrine (1:100,000; treatment LE, n = 9). Sensory block was evaluated through reaction to a painful mechanical stimulus applied at five sites on the limb. Motor block effect was evaluated according to visual gait assessments and thoracic limb vertical force measurements under dynamic and static conditions. Data were analyzed using repeated-measures generalized estimating equations. All statistical tests were performed two-sided at the α = 0.05 significance threshold. RESULTS: The duration of sensory block did not differ significantly between treatments. Visible gait impairment was more persistent in LE than in LI (118 ± 63 minutes for LI and 163 ± 23 minutes for LE; mean ± standard deviation) (p = 0.027). At nadir value, dynamic peak vertical force was lower in LE than in LI (p = 0.007). For both dynamic and static evaluations, the nadir and the return to baseline force were delayed in LE (return to normal at 180-200 minutes) when compared with LI (130-140 minutes) (p < 0.005). CONCLUSIONS AND CLINICAL RELEVANCE: The addition of epinephrine to lidocaine prolonged the duration and increased the intensity of the regional block, as verified by visual gait assessment and kinetic analysis. No significant difference was noted between treatments regarding sensory blockade. Kinetic analysis could be useful to evaluate regional anesthetic effect in dogs.

Analgesic efficacy of an oral transmucosal spray formulation of meloxicam alone or in combination with tramadol in cats with naturally occurring osteoarthritis.

OBJECTIVE: To evaluate the analgesic efficacy of meloxicam oral transmucosal spray (OTMS) alone and with tramadol in cats with osteoarthritis (OA). STUDY DESIGN: Randomized, blinded study. ANIMALS: Fifteen geriatric cats weighing 4.5 ± 1.0 kg. METHODS: Healthy cats with OA were randomly administered a placebo (every 12 hours orally) and meloxicam OTMS (approximately 0.05 mg kg-1 every 24 hours) (group M, n = 7), or tramadol (3 mg kg-1 every 12 hours orally) and meloxicam OTMS (group TM, n = 8) for 25 days. Evaluations performed before treatment (D0) and at week 3 (W3) consisted of peak vertical force, motor activity and response to mechanical temporal summation of pain (RMTS). Data were analyzed with mixed models and Fisher's exact test. RESULTS: Mean ± standard deviation peak vertical force (percentage of body weight) increased significantly in both groups (p = 0.02), from 47.7 ± 6.5% to 60.5 ± 9.4% in group M, and from 51.8 ± 5.0% to 64.1 ± 6.5% in group TM, with no difference between groups. Motor activity increased in M (from 43 ± 12 to 56 ± 13; p = 0.02), but not in TM. The number of stimulations from RMTS increased in TM only. Cut-off values were reached in a larger number of cats (n = 5) in TM than M (n = 1) (p < 0.05). Gastrointestinal adverse effects were self-limiting in six cats, including five in TM. CONCLUSIONS AND CLINICAL RELEVANCE: Meloxicam OTMS had similar effects on peak vertical force, motor activity and pain sensitization as previously reported for oral meloxicam in OA cats. The tramadol-meloxicam combination provided no evident benefit over meloxicam alone, except for central hypersensitivity (assessed with RMTS). Further assessment of the potential toxicity of the combination is required prior to clinical use. Gingival administration was well accepted overall.

Computational fluid dynamics characterization of blood flow in central aorta to pulmonary artery connections: importance of shunt angulation as a determinant of shear stress-induced thrombosis.

The central aortic shunt, consisting of a Gore-Tex (polytetrafluoroethylene) tube (graft) connecting the ascending aorta to the pulmonary artery, is a palliative operation for neonates with cyanotic congenital heart disease. These tubes often have an extended length, and therefore must be angulated to complete the connection to the posterior pulmonary arteries. Thrombosis of the graft is not uncommon and can be life-threatening. We have shown that a viscous fluid (such as blood) traversing a curve or bend in a small-caliber vessel or conduit can give rise to marked increases in wall shear stress, which is the major mechanical factor responsible for vascular thrombosis. Thus, the objective of this study was to use computational fluid dynamics to investigate whether wall shear stress (and shear rate) generated in angulated central aorta-to-pulmonary artery connections, in vivo, can be of magnitude and distribution to initiate platelet activation/aggregation, ultimately leading to thrombus formation. Anatomical features required to construct the computer-simulated blood flow pathways were verified from angiograms of central aortic shunts in patients. For the modeled central aortic shunts, we found wall shear stresses of (80-200 N/m(2)), with shear rates of (16,000-40,000/s), at sites of even modest curvature, to be high enough to cause platelet-mediated shunt thrombosis. The corresponding energy losses for the fluid transitions through the aorta-to-pulmonary connections constituted (70 %) of the incoming flow's mechanical energy. The associated velocity fields within these shunts exhibited vortices, eddies, and flow stagnation/recirculation, which are thrombogenic in nature and conducive to energy dissipation. Angulation-induced, shear stress-mediated shunt thrombosis is insensitive to aspirin therapy alone. Thus, for patients with central aortic shunts of longer length and with angulation, aspirin alone will provide insufficient protection against clotting. These patients are at risk for shunt thrombosis and significant morbidity and mortality, unless their anticoagulation regimen includes additional antiplatelet medications.

Clinical validity of outcome pain measures in naturally occurring canine osteoarthritis.

BACKGROUND: The conceptual validity of kinetic gait analysis and disability outcome assessment methods has guided their use in the assessment of pain caused by osteoarthritis (OA). No consensus on the best clinical methods for pain evaluation in canine OA exists, particularly, when evaluating treatments where a smaller treatment effect is anticipated than with pharmacological pain killers. This study thus aimed at determining the technical validity of some clinical endpoints on OA pain in dogs using the green-lipped mussel (GLM)-enriched diet.Twenty-three adult dogs with clinical OA completed the prospective controlled study. All the dogs were fed a balanced diet over a 30-day control period followed by a GLM-enriched diet over a 60-day period. The kinetic gait analysis parameter (PVF(BW), peak vertical force adjusted for body weight change), electrodermal activity (EDA), and a standardized multifactorial pain questionnaire (MFQ) were performed on day (D) 0 (inclusion), D30 (start) and D90 (end). The owners completed a client-specific outcome measures (CSOM) instrument twice a week. Motor activity (MA) was continuously recorded in seven dogs using telemetered accelerometric counts. We hypothesized that these methods would produce convergent results related to diet changes. A Type I error of 0.05 was adjusted to correct for the multiplicity of the primary clinical endpoints. RESULTS: Neither the EDA nor the MFQ were found reliable or could be validated. Changes in the PVFBW (P(adj) = 0.0004), the CSOM (P(adj) = 0.006) and the MA intensity (P(adj) = 0.02) from D0 to D90 suggested an effect of diet(s). Only the PVFBW clearly increased after the GLM-diet (P(adj) = 0.003). The CSOM exhibited a negative relationship with the PVF(BW) (P = 0.02) and MA duration (P = 0.02). CONCLUSIONS: The PVF(BW) exhibited the best technical validity for the characterization of the beneficial effect of a GLM-enriched diet. The CSOM and MA appeared less responsive following a GLM-diet, but these measures appeared complementary to gait analysis. Apparently, the CSOM provides the capacity to rely on pain OA assessment influenced by both lameness quantification (PVF(BW)) and physical functioning (MA).

Evaluation of osteoarthritis in cats: novel information from a pilot study.

OBJECTIVE: To describe structural changes associated with osteoarthritis (OA) in cats and to quantify OA-associated disability using functional evaluations. STUDY DESIGN: Cross-sectional pilot study with longitudinal data. ANIMALS: Normal cats (n = 2) and coxofemoral joint OA cats (n = 4) were evaluated by physical examination, radiography, and magnetic resonance imaging (MRI). METHODS: Structural changes related to OA were scored using computed radiographs (CR) and MRI. Functional evaluation consisted of podobarometric gait analyses performed using a pressure-sensitive mattress and motor activity assessments using collar-attached, accelerometer-based activity sensors. RESULTS: Structural scores for the coxofemoral joint OA-related lesions were lower in normal cats than OA cats for MRI (P = .07). Use of MRI allowed for whole-organ assessment of the coxofemoral joint. Pelvic limb peak vertical ground reaction force (PVF) was higher in normal cats than OA cats (P = .10). During the night, motor activity was greater in normal cats than OA cats (P = .04). PVF was positively correlated with mean motor activity (Spearman coefficient [Rho] = 0.83, P = .04) and negatively correlated with age and MRI structural score (Rho = -0.93 and -0.79, P < .01 and .06, respectively). CONCLUSIONS: This study provides the first description of OA-related lesions in cats using MRI. Gait analysis and accelerometry should be considered as objective tools to characterize OA-associated disability, although these assessments were weakly correlated with structural changes.

Owner-perceived signs and veterinary diagnosis in 50 cases of feline osteoarthritis.

Veterinarians contacted to identify cats diagnosed with osteoarthritis (OA) provided information on signalment, method of diagnosis, treatment and concurrent disease. Owners of 50 cats were interviewed to collect information on specific OA signs observed in the home, relating to mobility, self-maintenance, social and exploratory behavior, and activity and habits at diagnosis and after treatment. Mean age at diagnosis was 12 y; concurrent diseases were common (44%). Owner-reported abnormalities led to OA diagnosis in most cases; either as the primary finding (30%), or combined with abnormal physical examination or radiographic findings (64%). Owners frequently reported changes in mobility, particularly gait, jumping, and use of stairs. Oral or injectable disease-modifying osteoarthritis drugs were the most common treatments (71%). Feline OA diagnosis and therapeutic monitoring appear to rely heavily on owner-perceived signs; physical examination abnormalities may not be detected. Questioning of owners revealed various observable signs potentially useful in OA detection and monitoring.

Signes d'arthrose que perçoivent les propriétaires de chats. Des vétérinaires furent contactés pour identifier des cas d'arthrose féline, et ils ont fourni les informations concernant le signalement, la méthode de diagnostic et les traitements administrés à ces chats. Les propriétaires de 50 chats arthrosiques furent sondés pour caractériser les signes d'arthrose liés à la mobilité et l'activité, les soins du corps, le comportement exploratoire, et les habitudes particulières du chat au moment du diagnostic et suite au traitement. L'âge moyen était de 12,0 ans, et plusieurs chats avaient des maladies concomitantes (44 %). Le diagnostic est fondé sur les observations des propriétaires rapportées au vétérinaire compatibles avec de l'arthrose (30 %), ou sur leur recoupement avec les découvertes de l'examen physique ou radiographique (64 %). Les changements au niveau de la mobilité (surtout la démarche, le saut, et la façon de prendre les escaliers) étaient fréquents. Les traitements les plus fréquents étaient les agents structuro-modulateurs (71 %). Actuellement, les observations de changements subtils à la maison de la part du propriétaire sont utilisées pour le diagnostic et le suivi de l'arthrose féline, car des anomalies ne sont pas toujours évidentes lors de l'examen physique. Le questionnement précis des propriétaires a révélé d'autres signes potentiels d'arthrose féline.(Traduit par les auteurs).

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.

Automatic Quantification of Atherosclerosis in Contrast-Enhanced MicroCT Scans of Mouse Aortas Ex Vivo.

OBJECTIVE: While microCT evaluation of atherosclerotic lesions in mice has been formally validated, existing image processing methods remain undisclosed. We aimed to develop and validate a reproducible image processing workflow based on phosphotungstic acid-enhanced microCT scans for the volumetric quantification of atherosclerotic lesions in entire mouse aortas. Approach and Results. 42 WT and 42 apolipoprotein E knockout mouse aortas were scanned. The walls, lumen, and plaque objects were segmented using dual-threshold algorithms. Aortic and plaque volumes were computed by voxel counting and lesion surface by triangulation. The results were validated against manual and histological evaluations. Knockout mice had a significant increase in plaque volume compared to wild types with a plaque to aorta volume ratio of 0.3%, 2.8%, and 9.8% at weeks 13, 18, and 26, respectively. Automatic segmentation correlated with manual (r 2 ≥ 0.89; p < .001) and histological evaluations (r 2 > 0.96; p < .001). CONCLUSIONS: The semiautomatic workflow enabled rapid quantification of atherosclerotic plaques in mice with minimal manual work.

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).

Abaloparatide, a novel osteoanabolic PTHrP analog, increases cortical and trabecular bone mass and architecture in orchiectomized rats by increasing bone formation without increasing bone resorption.

Male osteoporosis can occur with advanced age and with hypogonadism, with increased bone resorption and/or inadequate bone formation contributing to reduced bone mass and increased fracture risk. Abaloparatide is a selective PTH receptor agonist that increases bone formation and bone mass in postmenopausal women with osteoporosis and in estrogen-deficient animals. The current study evaluated the effects of abaloparatide in orchiectomized (ORX) rats, a model of male osteoporosis. Four-month-old Sprague-Dawley rats underwent ORX or sham surgery; 8 weeks later the ORX groups exhibited relative osteopenia vs sham controls, based on dual X-ray absorptiometry (DXA) and/or peripheral quantitative computed tomography (pQCT) assessments at the total body, lumbar spine, femur, and tibia. ORX rats (n = 10/group) were then injected daily (s.c.) for 8 weeks with vehicle or abaloparatide at 5 (ABL5) or 25 µg/kg/d (ABL25). Sham controls (n = 10) received s.c. vehicle. DXA and pQCT showed that one or both abaloparatide groups gained more areal and volumetric BMD at all sites analyzed compared with vehicle controls, leading to substantial or complete reversal of ORX-induced BMD deficits. pQCT also indicated greater gains in tibial cortical thickness in both abaloparatide groups versus vehicle controls. Tibial bone histomorphometry showed greater trabecular bone formation and bone volume and improved micro-architecture with abaloparatide, with no increase in osteoclasts. Abaloparatide also led to significant improvements in the balance of biochemical bone formation markers versus bone resorption markers, which correlated with BMD changes. These findings suggest that abaloparatide may have therapeutic benefits in men with osteoporosis.

Refinement of the Montreal Instrument for Cat Arthritis Testing, for Use by Veterinarians: detection of naturally occurring osteoarthritis in laboratory cats.

Objectives Feline osteoarthritis causes pain and disability. Detection and measurement is challenging, relying heavily on owner report. This study describes refinement of the Montreal Instrument for Cat Arthritis Testing, for Use by Veterinarians. Methods A video analysis of osteoarthritic (n = 6) and non-osteoarthritic (n = 4) cats facilitated expansion of scale items. Three successive therapeutic trials (using gabapentin, tramadol and oral transmucosal meloxicam spray) in laboratory cats with and without natural osteoarthritis (n = 12-20) permitted construct validation (assessments of disease status sensitivity and therapeutic responsiveness) and further scale refinements based on performance. Results Scale osteoarthritic sensitivity improved from phase I to phase III; phase III scale total score ( P = 0.0001) and 4/5 subcategories - body posture ( P = 0.0006), gait ( P = 0.0031), jumping (0.0824) and global distance examination ( P = 0.0001) - detected osteoarthritic cats. Total score inter-rater (intra-class correlation coefficients [ICC] = 0.64-0.75), intra-rater (ICC = 0.90-0.91) and overall internal consistency (Cronbach's alpha = 0.85) reliability were good to excellent. von Frey anesthesiometer-induced paw withdrawal threshold increased with gabapentin in phase I, in osteoarthritic cats ( P <0.001) but not in non-osteoarthritic cats ( P = 0.075). Night-time activity increased during gabapentin treatment. Objective measures also detected tramadol and/or meloxicam treatment effects in osteoarthritic cats in phases II and III. There was some treatment responsiveness: in phase I, 3/10 subcategory scores improved ( P <0.09) in treated osteoarthritic cats; in phase II, 3/8 subcategories improved; and in phase III, 1/5 subcategories improved ( P <0.096). Conclusions and relevance The revised scale detected naturally occurring osteoarthritis, but not treatment effects, in laboratory cats, suggesting future potential for screening of at-risk cats. Further study is needed to confirm reliability, validity (disease sensitivity and treatment responsiveness) and clinical feasibility, as well as cut-off scores for osteoarthritic vs non-osteoarthritic status, in client-owned cats.

Computational fluid dynamics characterization of pulsatile flow in central and Sano shunts connected to the pulmonary arteries: importance of graft angulation on shear stress-induced, platelet-mediated thrombosis.

OBJECTIVES: Central (aorta) and Sano (right ventricle)-to-pulmonary artery (PA) shunts, palliative operations for infants with complex heart defects, can develop life-threatening thrombosis. We employed computational fluid dynamics (CFD) to study pulsatile flow in these shunts, with the goal to identify haemodynamic characteristics conducive to thrombus formation. METHODS: CFD, using the finite volume method with cardiac catheterization data, and computer simulations, based on angiography, were employed to determine flow-velocity field, wall shear stress (WSS) profile and oscillatory shear index (OSI). RESULTS: At prominent angulation, in central shunts (4 and 3.5 mm), WSS reached 245 and 123 (Pascal-Pa), peak systole and 137 and 46 Pa, end diastole; and, in Sano shunts (5 and 6 mm), WSS attained 203 and 133 Pa, peak systole and 1.6 and 1.5 Pa, end diastole. Counter-rotating flow vortices augmented WSS. These high WSSs can promote platelet aggregation, leading to thrombus formation. The OSIs averaged 0.39, indicative of multidirectional shearing forces. Shunt burden was assessed by averaging WSS, over its luminal area and the cardiac cycle. For the central shunts, these WSSs were 73.0 and 67.2 Pa; whereas, for the Sano shunts, 34.9 and 19.6 Pa. For modified Blalock-Taussig shunts (4 and 3.5 mm), the averaged WSSs were significantly lower at 26.0 and 27.5 Pa, respectively. CONCLUSIONS: CFD modelling is an important tool to determine blood flow behaviour in shunts. Graft angulation presents a risk for shear stress-induced, platelet- mediated thrombosis, which is more likely to occur in elongated central than in Sano shunts.

Spinal neuropeptide modulation, functional assessment and cartilage lesions in a monosodium iodoacetate rat model of osteoarthritis.

BACKGROUND AND AIMS: Characterising the temporal evolution of changes observed in pain functional assessment, spinal neuropeptides and cartilage lesions of the joint after chemical osteoarthritis (OA) induction in rats. METHODS AND RESULTS: On day (D) 0, OA was induced by an IA injection of monosodium iodoacetate (MIA). Rats receiving 2mg MIA were temporally assessed at D3, D7, D14 and D21 for the total spinal cord concentration of substance P (SP), calcitonin gene related-peptide (CGRP), bradykinin (BK) and somatostatin (STT), and for severity of cartilage lesions. At D21, the same outcomes were compared with the IA 1mg MIA, IA 2mg MIA associated with punctual IA injection of lidocaine at D7, D14 and D21, sham (sterile saline) and naïve groups. Tactile allodynia was sequentially assessed using a von Frey anaesthesiometer. Non-parametric and mixed models were applied for statistical analysis. Tactile allodynia developed in the 2mg MIA group as soon as D3 and was maintained up to D21. Punctual IA treatment with lidocaine counteracted it at D7 and D14. Compared to naïve, [STT], [BK] and [CGRP] reached a maximum as early as D7, which plateaued up to D21. For [SP], the increase was delayed up to D14 and maintained at D21. No difference in levels of neuropeptides was observed between MIA doses, except for higher [STT] in the 2mg MIA group (P=0.029). Neuropeptides SP and BK were responsive to lidocaine treatment. The increase in severity of cartilage lesions was significant only in the 2mg MIA groups (P=0.01). CONCLUSION: In the MIA OA pain model, neuropeptide modulation appears early, and confirms the central nervous system to be an attractive target for OA pain quantification. The relationship of neuropeptide release with severity of cartilage lesions and functional assessment are promising and need further validation.

Pharmacokinetics of Lidocaine Hydrochloride Administered with or without Adrenaline for the Paravertebral Brachial Plexus Block in Dogs.

Adrenaline is known to prolong the duration of local anesthesia but its effects on the pharmacokinetic processes of local anesthetic drugs are not fully understood. Our objective was to develop a compartmental model for quantification of adrenaline's impact on the pharmacokinetics of perineurally-injected lidocaine in the dog. Dogs were subjected to paravertebral brachial plexus block using lidocaine alone or adrenalinated lidocaine. Data was collected through a prospective, randomised, blinded crossover protocol performed over three periods. Blood samples were collected during 180 minutes following block execution. Compartmental pharmacokinetic models were developed and their goodness-of-fit were compared. The lowering effects of adrenaline on the absorption of lidocaine were statistically determined with one-sided tests. A one-compartment disposition model with two successive zero-order absorption processes best fitted our experimental data. Adrenaline decreased the peak plasma lidocaine concentration by approximately 60% (P < 0.001), decreased this local anesthetic's fast and slow zero-order absorption rates respectively by 50% and 90% (P = 0.046, and P < 0.001), which respective durations were prolonged by 90% and 1300% (P < 0.020 and P < 0.001). Lidocaine demonstrated a previously unreported atypical absorption profile following its paravertebral injection in dogs. Adrenaline decreased the absorption rate of lidocaine and prolonged the duration of its absorption.