Efficacy and effects of various anti-crib devices on behaviour and physiology of crib-biting horses.

REASONS FOR PERFORMING STUDY: Crib-biting is a common oral stereotypy. Although most treatments involve prevention, the efficacy of various anti-crib devices, including surgically implanted gingival rings, has thus far not been empirically tested. OBJECTIVES: Demonstrate the effect that 2 anti-crib collars, muzzle and gingival rings have on crib-biting, other maintenance behaviours, and cortisol levels in established crib-biting horses. STUDY DESIGN: Randomised, crossover clinical trial. METHODS: In Experiment I, 2 anti-crib collars and a muzzle were used on 8 established crib-biting horses; horses wore each of 3 devices for 7 days, with a 7-day device-free period between treatments. Horses were video recorded for 24 h at least 3 times each week prior to any device placement, and always the day after a device was removed. In Experiment II, gingival rings were used in 6 established crib-biting horses; horses were video recorded for 3 days prior to ring implantation and the day after surgery until the rings became ineffective. Plasma cortisol levels were assessed every day during Experiment II and on Days 1, 3 and 5 of each week during Experiment I. RESULTS: All devices significantly reduced crib-biting compared with control periods. There was no significant difference in crib-bite reduction amongst devices in Experiment I, or between pre-device periods and the first day the device was removed. The only increase in plasma cortisol occurred on the day of surgery in Experiment II. CONCLUSIONS: Common anti-crib devices are effective in reducing crib-biting and significant distress was not evident from our findings. We did not find a post inhibitory rebound effect. Surgical rings were successful only temporarily and implantation was probably painful to the horses. Because stereotypies involve suboptimal environmental conditions, efforts should be made to improve husbandry factors previously shown to contribute to crib-biting, and research into decreasing horses' motivation to crib-bite should continue.

Synthesis and SAR of bicyclic heteroaryl hydroxamic acid MMP and TACE inhibitors.

Potent and selective bicyclic heteroaryl hydroxamic acid MMP and TACE inhibitors were synthesized by a novel convergent route. Selectivity and efficacy versus MMPs and TACE could be controlled by appropriate substitution on the scaffolds and by variation of the P1' group. Select compounds were found to be effective in in vivo models of arthritis.

Meniscal allograft transplantation. Two- to eight-year results.

We evaluated 18 of 23 patients who had undergone cryopreserved meniscal allograft transplantation for compartmental pain after total meniscectomy 2 to 8 years (mean, 5.4) after the operation. The Short Form-36 scores revealed a decrease in pain with a significant improvement in function, although function remained limited. There was no significant decrease in joint space on 45 degrees posteroanterior weightbearing radiographs through the duration of the study. Eight of 22 allograft menisci (36%) tore during the study period, necessitating 6 partial and 2 total meniscectomies. Two patients subsequently underwent reimplantation. Histologic examination of the removed tissue revealed reduced cellularity as compared with normal or torn native menisci. Four specimens also underwent detailed cytokine evaluation and demonstrated reduced cytokine expression compared with controls. While successful in alleviating compartmental pain that may be a late consequence of major meniscectomy, allograft menisci are repopulated with fewer cells than are present in normal or torn native menisci. These cells also demonstrate potentially reduced function, as measured by decreased growth factor production. This decreased biologic activity may be a factor that contributes to the high frequency of retears noted in this and prior studies.

Design and synthetic considerations of matrix metalloproteinase inhibitors.

Experimental evidence confirms that the matrix metalloproteinases (MMPs) play a fundamental role in a wide variety of pathologic conditions that involve connective tissue destruction including osteoarthritis and rheumatoid arthritis, tumor metastasis and angiogenesis, corneal ulceration, multiple sclerosis, periodontal disease, and atherosclerosis. Modulation of MMP regulation is possible at several biochemical sites, but direct inhibition of enzyme action provides a particularly attractive target for therapeutic intervention. Hypotheses concerning inhibition of specific MMP(s) with respect to disease target and/or side-effect profile have emerged. Examples are presented of recent advances in medicinal chemistry approaches to the design of matrix metalloproteinase inhibitors (MMPIs), approaches that address structural requirements and that influence potency, selectivity, and bioavailability. Two important approaches to the design, synthesis, and biological evaluation of MMPIs are highlighted: (1) the invention of alternatives to hydroxamic acid zinc chelators and (2) the construction of nonpeptide scaffolds. One current example in each of these two approaches from our own work is described.

The synthesis and biological activity of a novel series of diazepine MMP inhibitors.

A novel series of diazepine-based hydroxamic acid inhibitors of MMP-1, MMP-9, and MMP-13 were prepared and evaluated both in vitro and in vivo.