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.

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.

Efficacy and Safety of FX201, a Novel Intra-Articular IL-1Ra Gene Therapy for Osteoarthritis Treatment, in a Rat Model.

Osteoarthritis (OA) is a disabling, degenerative disease characterized by progressive cartilage and bone damage. There remains a need for local therapies that, following a single injection, can provide long-term pain relief and functional improvement and potentially delay disease progression. FX201 is a novel, intra-articular (IA), interleukin-1 receptor antagonist (IL-1Ra) gene therapy in development for the treatment of OA. In this study, we assessed the efficacy, biodistribution, and safety of helper-dependent adenovirus (HDAd)-ratIL-1Ra, the rat surrogate of FX201, and the biodistribution of FX201, in the anterior cruciate ligament transection (ACLT) rat OA model. A single IA injection of HDAd-ratIL-1Ra administered 7 days post-ACLT mitigated OA-related changes to cartilage, bone, and the synovial membrane at week 12 following surgery. Furthermore, FX201 and HDAd-ratIL-1Ra persisted for at least 92 days in the injected joint and proximal tissues with minimal evidence of vector spreading peripherally. Finally, HDAd-ratIL-1Ra showed a favorable safety profile without any local or systemic adverse effects. In conclusion, HDAd-ratIL-1Ra demonstrated local therapeutic and disease-modifying effects and was well tolerated, supporting further clinical development of FX201.

The Society of Toxicologic Pathology: Advances and Adventures in the First 50 Years.

The Society of Toxicologic Pathology (STP, https://www.toxpath.org/) was founded in North America in 1971 as a nonprofit scientific and educational association to promote the professional practice of pathology as applied to pharmaceutical and environmental safety assessment. In the ensuing 50 years, the STP has become a principal global leader in the field. Society membership has expanded to include toxicologic pathologists and allied scientists (eg, toxicologists, regulatory reviewers) from many nations. In addition to serving membership needs for professional development and networking, major STP outreach activities include production of articles and presentations designed to optimize toxicologic pathology procedures ("best practice" recommendations), communicate core principles of pathology evaluation and interpretation ("points to consider" and "opinion" pieces), and participation in international efforts to harmonize diagnostic nomenclature. The STP has evolved into an essential resource for academic, government, and industrial organizations that employ and educate toxicologic pathologists as well as use toxicologic pathology data across a range of applications from assessing product safety (therapies, foods, etc) to monitoring and maintaining environmental and occupational health. This article recapitulates the important milestones and accomplishments of the STP during its first 50 years.

Proof of Concept for a Deep Learning Algorithm for Identification and Quantification of Key Microscopic Features in the Murine Model of DSS-Induced Colitis.

Inflammatory bowel disease (IBD) is a complex disease which leads to life-threatening complications and decreased quality of life. The dextran sulfate sodium (DSS) colitis model in mice is known for rapid screening of candidate compounds. Efficacy assessment in this model relies partly on microscopic semiquantitative scoring, which is time-consuming and subjective. We hypothesized that deep learning artificial intelligence (AI) could be used to identify acute inflammation in H&E-stained sections in a consistent and quantitative manner. Training sets were established using ×20 whole slide images of the entire colon. Supervised training of a Convolutional Neural Network (CNN) was performed using a commercial AI platform to detect the entire colon tissue, the muscle and mucosa layers, and 2 categories within the mucosa (normal and acute inflammation E1). The training sets included slides of naive, vehicle-DSS and cyclosporine A-DSS mice. The trained CNN was able to segment, with a high level of concordance, the different tissue compartments in the 3 groups of mice. The segmented areas were used to determine the ratio of E1-affected mucosa to total mucosa. This proof-of-concept work shows promise to increase efficiency and decrease variability of microscopic scoring of DSS colitis when screening candidate compounds for IBD.

A study in a rat initiation-promotion bladder tumour model demonstrated no promoter/progressor potential of dapagliflozin.

Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, is indicated to improve glycaemic control in adults of type 2 diabetes. In nonclinical studies, dapagliflozin was neither genotoxic nor carcinogenic. However, in some clinical studies, an increased incidence of bladder cancer was observed in the dapagliflozin group vs. the placebo. Therefore, this study was undertaken to determine if dapagliflozin can act as a promoter in a 2-stage bladder cancer model in rats induced with N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN). Rats given BBN (100 or 400 mg/kg, po) twice weekly for 6 weeks in Phase 1 were assigned in Phase 2 to receive daily dose of vehicle, dapagliflozin (0.5 mg/kg, po) or uracil (positive control, 3% in diet) from weeks 8-34. All bladders were evaluated by histopathology. Verifying the validity of the model, uracil increased the incidence of bladder cancer, while dapagliflozin had no effect on the incidence or invasiveness of transitional cell carcinoma. The exposure of dapagliflozin at 0.5 mg/kg/day in rats was 7 times the clinical exposure at maximal therapeutic dose (10 mg). In conclusion, dapagliflozin does not act as promoter or progressor of bladder cancer in a validated bladder cancer model in rats.

Syndrome of inappropriate antidiuretic hormone secretion in a dog with a histiocytic sarcoma.

A 7-year-old female neutered Bernese mountain dog was presented in a semi-comatose state. Based on serum hypo-osmolality with inappropriate urine hyper-osmolality and urine sodium excretion, the dog was diagnosed with a syndrome of inappropriate antidiuretic hormone secretion secondary to a histiocytic sarcoma. This report describes the first case of this syndrome in a dog with histiocytic sarcoma.

Syndrome de sécrétion inappropriée d'hormone antidiurétique chez un chien avec un sarcome histiocytaire. Une chienne stérilisée de 7 ans, Bouvier bernois, est présentée dans un état semi-comateux. Basé sur une hypo-osmolalité sérique associée à une hyper-osmolalité urinaire et une excrétion sodique urinaire toutes deux inappropriées, un diagnostic de syndrome de sécrétion inappropriée d'hormone antidiurétique secondaire à un sarcome histiocytaire est posé. Ce cas est le premier cas de ce syndrome chez un chien avec un sarcome histiocytaire.(Traduit par les auteurs).

Salt Selection Matters: Differential Renal Toxicity With MDV1634.Maleate Versus MDV1634.2HCl.

Salt forms of pharmaceutical compounds can have unique pharmacokinetic and toxicity properties. MDV1634 was evaluated for neurology indication and also demonstrated blood pressure (BP)-lowering effects in nonclinical studies. During the chemistry manufacturing campaign, 2 salt forms, dihydrochloride (2HCl) and maleate (MAL), which improved chemical stability and water solubility of the free base were identified. MDV1634.MAL showed better chemical attributes and was evaluated in toxicology studies for further development. A 28-day oral toxicity study in dogs with MDV1634.MAL demonstrated partially reversible renal toxicity. Although MAL salt is generally regarded as safe, renal toxicity is sometimes observed in rats and dogs. To evaluate contribution of each salt form to renal toxicity and BP lowering, an additional 28-day study was conducted with MDV1634.2HCL and MDV1634.MAL, which included toxicokinetics, continuous BP measurement in a subset of dogs, and sensitive urinary biomarker evaluation for temporal monitorability and reversibility of potential renal findings. In the repeat study, both salt forms showed similar exposures during the dosing period, but renal tubular toxicity was observed only with MDV1634.MAL and not with MDV1634.2HCl. The renal findings with MDV1634.MAL included early urinary biomarker changes (increase in albumin, clusterin, ß2 microglobulin, and neutrophil gelatinase-associated lipocalin); elevations in serum blood urea nitrogen and creatinine; and microscopic findings of partially reversible tubular basophilia, single cell necrosis, pigmentation, and mineralization. The renal findings in contrast to the BP findings were MAL-specific and considered not related to MDV1634, thereby under scoring the importance of salt forms in pharmaceutical development.

Chronic desmitis and enthesiophytosis of the radio-ulnar interosseous ligament in a dog.

A 10-year-old golden retriever dog was presented for chronic right forelimb lameness associated with a painful swelling at the lateral aspect of the proximal ulna. Proximal ulnar ostectomy and stabilization resulted in a good clinical outcome. The proposed diagnosis is chronic desmitis and enthesiophytosis of the radio-ulnar interosseous ligament.

Desmite chronique et enthésiophytose du ligament interosseux radio-ulnaire chez un chien. Un Golden retriever de 10 ans a été présenté pour boiterie chronique du membre thoracique droite associée à un gonflement douloureux à l'aspect latéral de l'ulna proximal. Une ostéotomie ulnaire proximale avec stabilisation ont permit un bon résultat clinique. Le diagnostic proposé est une desmite chronique et enthésiophytose du ligament interosseux radio-ulnaire.(Traduit par Isabelle Vallières).

Clinical significance of renal pelvic dilatation on ultrasound in dogs and cats.

Renal pelvic dilatation is often recognized sonographically in dogs and cats, but ranges of measurements expected with different urologic conditions remain unknown. Ultrasound images of 81 dogs and 66 cats with renal pelvic dilatation were reviewed, and six groups were formed based on medical records: (I) clinically normal renal function, and (II) clinically normal renal function with diuresis; (III) pyelonephritis; (IV) noninfectious renal insufficiency; (V) outflow obstruction; (VI) miscellaneous nonobstructive anomalies. Medians for maximal pelvic width (range) for group I was 2.0 mm (1.0-3.8) in 11 dogs, and 1.6 mm (0.8-3.2) in 10 cats; for group II, 2.5 mm (1.3-3.6) in 15 dogs, and 2.3mm (1.1-3.4) in 16 cats; for group III, 3.6 mm (1.9-12.0) in nine dogs, and 4.0 mm (1.7-12.4) in seven cats; for group IV, 3.1 mm (0.5-10.8) in 33 dogs, and 2.8 mm (1.2-7.3) in 13 cats; for group V, 15.1mm (5.1-76.2) in six dogs, and 6.8mm (1.2-39.1) in 17 cats; and for group VI, 3.8mm (1.2-7.6) in seven dogs, and 3.0 mm (1.3-7.5) in three cats. Pelvic width in group I was lower than in groups III-V (P = 0.0001), but did not significantly differ from group II. Pelvic width > or =13 mm always indicated obstruction. While the proportion of bilateral pelvic dilatation was not different among groups, the difference in pelvic width (maximal-minimal) was greater in group V vs. groups I, II, and IV (P = 0.0009). These results confirm that renal pelvic dilatation can be detected sonographically in dogs and cats with clinically normal renal function, and that it increases with renal insufficiency, pyelonephritis, or outflow obstruction. Nevertheless, renal pelvic width varies substantially within groups and should be interpreted with caution.