Characterization of the use of shock wave therapy among equine veterinarians.

Extracorporeal shock wave therapy (ESWT) research has prioritized mechanism of action and efficacy. Data regarding frequency of use and clinical opinion are not available. A web-based survey was offered to members of the American Association of Equine Practitioners; 144 responses were obtained. Frequency of ESWT use by respondents was as follows: daily by 8.3% (12/144), at least once weekly by 36.8% (53/144), at least once per month by 22.9% (33/144), less than once per month by 19.4% (28/144), and never by 12.5% (18/144) of respondents. The most common reason for use was to treat ligamentous injuries. Opinion of efficacy was variable.

La recherche sur la thérapie extra-corporelle par ondes de choc (ESWT) a priorisé le mécanisme d'action et l'efficacité. Les données concernant la fréquence d'utilisation et l'opinion clinique ne sont pas disponibles. Un sondage sur le web fut offert aux membres de l'American Association of Equine Practitionners; 144 réponses furent obtenues. La fréquence d'utilisation d'ESWT par les répondants était la suivante : quotidiennement par 8,3 % (12/144), au moins une fois semaine par 36,8 % (53/144), au moins une fois par mois 22,9 % (33/144), moins d'une fois par mois par 19,4 % (28/144) et jamais par 12,5 % (18/144) des répondants. La raison la plus fréquente pour son utilisation était pour traiter des blessures aux ligaments. Les opinions sur son efficacité étaient variables.(Traduit par Dr Serge Messier).

Sacrococcygeal luxation and complete tail amputation following a tail pull injury in a horse.

A 17-year-old Quarter horse mare was presented because of traumatic luxation of the fifth sacral and first coccygeal vertebrae resulting in loss of sensation, motor function, and perfusion of the tail. The case was complicated by an associated tail head hematoma. Due to the severity of the injury, tail amputation was performed at the level of the luxation. Tail amputations in horses at the sacrococcygeal junction following a suspected tail pull injury are infrequently reported in the literature.

Luxation sacrococcygienne et amputation complète de la queue à la suite d'une blessure par traction de la queue chez un cheval. Une jument Quarter horse âgée de 17 ans fut présentée pour cause de luxation traumatique de la cinquième vertèbre sacrée et de la première vertèbre coccygienne résultant en une perte de sensation, de fonction moteur, et de perfusion de la queue. Le cas était compliqué par l'association d'un hématome de la tête de la queue. Compte tenu de la sévérité de la blessure, l'amputation de la queue fut effectuée au site de la luxation. Les amputations de la queue chez les chevaux à la jonction sacrococcygienne à la suite d'une blessure suspectée causée par traction de la queue ne sont rapportées que peu fréquemment dans la littérature.(Traduit par Dr Serge Messier).

Second carpal bone slab fracture and subluxation of the middle carpal joint in a horse subsequent to arthrodesis of the carpometacarpal joint.

OBJECTIVE: To report complications of arthrodesis of the carpometacarpal (CMC) joint using a drilling technique in an adult horse. STUDY DESIGN: Case report. ANIMALS: Horse (n = 1). METHOD: A 12-year-old Quarter Horse mare with CMC osteoarthritis (CMC-OA) had arthrodesis under general anesthesia in right lateral recumbency. Under fluoroscopic guidance, a 4.5 mm drill bit was inserted at 3 drilling sites 5-6 cm into the CMC joint and was fanned 30-45° in the plane of the joint and 5-10° in the long axis of the limb to destroy articular cartilage and expose the subchondral bone. RESULTS: The horse presented 2 weeks after surgery for severe lameness of the operated limb. A slab fracture of the 2nd carpal bone (C2) and subluxation of the middle carpal (MC) joint was diagnosed. The horse was humanely euthanatized due to poor prognosis. CONCLUSION: The fanning technique of arthrodesis of the CMC joint may lead to fracture of carpal bones, joint instability, and MC joint subluxation. A balance between articular surface destruction and maintenance of joint stability should be achieved when using this technique.

Mandibular condylectomy in a cow with a chronic luxation of the temporomandibular joint.

A cow, presented after being struck by a motor vehicle, continued to have difficulty eating after mandibular fracture repair. Imaging showed a temporomandibular luxation and a mandibular condylectomy was performed. Mastication improved greatly but the cow was euthanized due to infection. This is the first report of mandibular condylectomy in cattle.

Condylectomie mandibulaire chez une vache avec une luxation chronique de l'articulation temporomandibulaire. Une vache présentée après avoir été heurtée par un véhicule automobile, continuait d'éprouver de la difficulté à manger après la réparation d'une fracture mandibulaire. L'imagerie a indiqué une luxation temporo-mandibulaire et une condylectomie mandibulaire a été réalisée. La mastication s'est améliorée considérablement mais la vache a été euthanasiée en raison d'une infection. Il s'agit du premier rapport d'une condylectomie mandibulaire chez les bovins.(Traduit par Isabelle Vallières).

Discovery of Potent, Orally Bioavailable, Tricyclic NLRP3 Inhibitors.

NLRP3 is a molecular sensor recognizing a wide range of danger signals. Its activation leads to the assembly of an inflammasome that allows for activation of caspase-1 and subsequent maturation of IL-1ß and IL-18, as well as cleavage of Gasdermin-d and pyroptotic cell death. The NLRP3 inflammasome has been implicated in a plethora of diseases including gout, type 2 diabetes, atherosclerosis, Alzheimer's disease, and cancer. In this publication, we describe the discovery of a novel, tricyclic, NLRP3-binding scaffold by high-throughput screening. The hit (1) could be optimized into an advanced compound NP3-562 demonstrating excellent potency in human whole blood and full inhibition of IL-1ß release in a mouse acute peritonitis model at 30 mg/kg po dose. An X-ray structure of NP3-562 bound to the NLRP3 NACHT domain revealed a unique binding mode as compared to the known sulfonylurea-based inhibitors. In addition, NP3-562 shows also a good overall development profile.

Crystal Structure of NLRP3 NACHT Domain With an Inhibitor Defines Mechanism of Inflammasome Inhibition.

The NLRP3 inflammasome assembles in response to a variety of pathogenic and sterile danger signals, resulting in the production of interleukin-1ß and interleukin-18. NLRP3 is a key component of the innate immune system and has been implicated as a driver of a number of acute and chronic diseases. We report the 2.8 Å crystal structure of the NLRP3 NACHT domain in complex with an inhibitor. The structure defines a binding pocket formed by the four subdomains of the NACHT domain, and shows the inhibitor acts as an intramolecular glue, which locks the protein in an inactive conformation. It provides further molecular insight into our understanding of NLRP3 activation, helps to detail the residues involved in subdomain coordination within the NLRP3 NACHT domain, and gives molecular insights into how gain-of-function mutations de-stabilize the inactive conformation of NLRP3. Finally, it suggests stabilizing the auto-inhibited form of the NACHT domain is an effective way to inhibit NLRP3, and will aid the structure-based development of NLRP3 inhibitors for a range of inflammatory diseases.

Tetracyclic indole inhibitors of hepatitis C virus NS5B-polymerase.

We report the evolutionary path from an open-chain series to conformationally constrained tetracyclic indole inhibitors of HCV NS5B-polymerase, where the C2 aromatic is tethered to the indole nitrogen. SAR studies led to the discovery of zwitterionic compounds endowed with good intrinsic enzyme affinity and cell-based potency, as well as superior DMPK profiles to their acyclic counterparts, and ultimately to the identification of a pre-clinical candidate with an excellent predicted human pharmacokinetic profile.

Discovery of (7R)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (MK-3281), a potent and orally bioavailable finger-loop inhibitor of the hepatitis C virus NS5B polymerase.

Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain. Structure-activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate. The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.