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The role of an epithelial neutrophil-activating peptide-78-like protein in rat adjuvant-induced arthritis.

The chemokine, epithelial neutrophil-activating peptide-78 (ENA-78), is a potent neutrophil chemotaxin whose expression is increased in inflamed synovial tissue and fluid in human rheumatoid arthritis compared with osteoarthritis. Since ENA-78 has been implicated in the pathogenesis of RA, we examined the expression of an ENA-78-like protein during the development of rat adjuvant-induced arthritis (AIA). Using an ELISA assay, we found increased levels of antigenic ENA-78-like protein in the sera of AIA animals compared with control normal animals by day 7 postadjuvant injection. ENA-78-like protein levels continued to increase as AIA developed. ENA-78-like protein levels in joint homogenates were increased in AIA animals later in the development of the disease, by day 18 during maximal arthritis, compared with control animals. Expression of ENA-78-like protein in both the AIA serum and joint correlated with the progression of inflammation of the joints. Anti-human ENA-78 administered before disease onset modified the severity of AIA, while administration of anti-ENA-78 after clinical onset of AIA did not modify the disease. These data support a role for an ENA-78-like protein as an important chemokine in the progression and maintenance of AIA.

Animals↗

Nutritional secondary hyperparathyroidism in free-living fledgling American crows (Corvus brachyrhynchos brachyrhynchos).

From June 1994 to June 1996, 18 fledgling American crows (Corvus brachyrhynchos brachyrhynchos) from multiple locations on Long Island, New York, were presented with signs of metabolic bone disease characterized by folding fractures of the proximal tibiotarsus. Plasma alkaline phosphatase levels were elevated, and the calcium/phosphorus ratio and 25-hydroxycholecalciferol (25-(OH)D3) levels were decreased. The histopathologic diagnosis was parathyroid hyperplasia and generalized osteodystrophia fibrosa. A diet low in bioavailable calcium and/or vitamin D3 was the probable cause. Also, exposure to xenobiotics could have contributed to the depression of 25-(OH)D3 levels.

Animals↗

Antiarthritic activity of soluble tumor necrosis factor receptor type I forms in adjuvant arthritis: correlation of plasma levels with efficacy.

OBJECTIVE: To determine the importance of tumor necrosis factor (TNF) in the pathogenesis of adjuvant disease in rats and to determine plasma levels of recombinant soluble TNF receptor type I (sTNF-RI) necessary for efficacy, to project dosing for human clinical trials. METHODS: Rats with adjuvant arthritis were treated by continuous infusion with sTNF-RI forms to maintain blood levels of this TNF-alpha inhibitory protein. In addition, rats were given bolus injections of polyethylene glycol linked sTNF-RI and efficacy and plasma levels were determined. Effects of treatment in the rats were monitored by sequential volume or diameter measurement of ankle joints, final paw weights, and histologic evaluation of ankle joints, with particular emphasis on bone erosive lesions. RESULTS: In all studies and regardless of dosing methodology (bolus vs continuous infusion), minimal plasma levels for efficacy were in the 0.3-0.5 microg/ml range. Higher plasma levels resulted in greater efficacy, with maximal effects achieved when plasma levels were in the 5 microg/ml range. Beneficial effects of treatment were seen on body weight, paw swelling, splenomegaly, hepatomegaly, and bone resorption. CONCLUSION: TNF-alpha is an important mediator of all aspects of rat adjuvant disease including both the destructive processes in the joints as well as the systemic manifestations of adjuvant disease. Studies using various forms of sTNF-RI consistently show that plasma levels of 0.3-0.5 microg/ml are required for minimal efficacy and that higher plasma levels show dose-responsive enhanced efficacy.

Animals↗

Amelioration of type II collagen induced arthritis in rats by treatment with sodium diethyldithiocarbamate.

OBJECTIVE: Sodium diethyldithiocarbamate (Ditiocarb, DDTC), which is used in the treatment of heavy metal poisoning, effectively inhibits NF-kappaB activation and cytokine secretion in vitro. To investigate the antiinflammatory and immunosuppressive potency of DDTC, we examined its influence on the course of collagen induced arthritis in rats. METHODS: Arthritis was induced in female DA rats by injection of rat collagen type II emulsified in incomplete Freund's adjuvant into the tail base. After onset of arthritis, the animals received DDTC or vehicle by intraperitoneal injections or subcutaneous infusion using osmotic pumps. Disulfiram, which is cleaved into DDTC within the gastrointestinal tract, was administered orally via gastric gavage. The course of arthritis was followed by clinical scoring and measurement of joint swelling. RESULTS: Collagen induced arthritis was significantly ameliorated by intraperitoneal injection (2 x 300 mg/kg/day) and subcutaneous infusion (120 mg/kg/day) of DDTC and by enteral administration of disulfiram (200 and 300 mg/kg/day). CONCLUSION: Dithiocarbamates may provide an effective new approach for the treatment of arthritis and other inflammatory diseases.

Animals↗

[Navicular disease in the hind limb of a Warmblood horse].

A 12-year-old Dutch Warmblood mare was admitted to the clinic with a 1-month history of lameness of the left hind leg. After clinical and radiological examinations and an bursascopy, the diagnosis navicular disease was made. The therapy consisted of stallrest, non-steroidal anti-inflammatory drugs, and orthopaedic shoeing plus intrabursal injections of short-acting corticosteroids and hyaluronic acid. The therapy was repeated following recurrence of the lameness. According to the owner the horse is currently performing at its previous level.

Administration, Oral↗

IL-1 alpha beta blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas TNF-alpha blockade only ameliorates joint inflammation.

Anti-TNF-alpha treatment of rheumatoid arthritis patients markedly suppresses inflammatory disease activity, but so far no tissue-protective effects have been reported. In contrast, blockade of IL-1 in rheumatoid arthritis patients, by an IL-1 receptor antagonist, was only moderately effective in suppressing inflammatory symptoms but appeared to reduce the rate of progression of joint destruction. We therefore used an established collagen II murine arthritis model (collagen-induced arthritis(CIA)) to study effects on joint structures of neutralization of either TNF-alpha or IL-1. Both soluble TNF binding protein and anti-IL-1 treatment ameliorated disease activity when applied shortly after onset of CIA. Serum analysis revealed that early anti-TNF-alpha treatment of CIA did not decrease the process in the cartilage, as indicated by the elevated COMP levels. In contrast, anti-IL-1 treatment of established CIA normalized COMP levels, apparently alleviating the process in the tissue. Histology of knee and ankle joints corroborated the finding and showed that cartilage and joint destruction was significantly decreased after anti-IL-1 treatment but was hardly affected by anti-TNF-alpha treatment. Radiographic analysis of knee and ankle joints revealed that bone erosions were prevented by anti-IL-1 treatment, whereas the anti-TNF-alpha-treated animals exhibited changes comparable to the controls. In line with these findings, metalloproteinase activity, visualized by VDIPEN production, was almost absent throughout the cartilage layers in anti-IL-1-treated animals, whereas massive VDIPEN appearance was found in control and sTNFbp-treated mice. These results indicate that blocking of IL-1 is a cartilage- and bone-protective therapy in destructive arthritis, whereas the TNF-alpha antagonist has little effect on tissue destruction.

Animals↗

Effects of PEGylated soluble tumor necrosis factor receptor type I (PEG sTNF-RI) alone and in combination with methotrexate in adjuvant arthritic rats.

OBJECTIVE: To determine the potential combination benefit of treatment with PEG sTNF-RI and methotrexate in adjuvant arthritic rats. METHODS: Lewis rats with adjuvant arthritis were treated by sc injections of either 3.0 or 0.3 mg/kg PEG sTNF-RI on days 9, 11, and 13 of adjuvant arthritis. The effects of PEG sTNF-RI treatment alone were compared to treatment with daily oral methotrexate (0.075, 0.06 or 0.045 mg/kg) or methotrexate in combination with PEG sTNF-RI. Efficacy was monitored by volume measurement of ankle joints, final paw weights and histologic evaluation with particular emphasis on bone lesions. RESULTS: Treatment with 3.0 or 0.3 mg/kg PEG sTNF-RI alone resulted in 52% or 28% inhibition, respectively, of paw swelling as assessed by final paw weight. Treatment with methotrexate at either 0.075, 0.06, or 0.045 mg/kg gave 84%, 51% or 18% inhibition and combination treatment resulted in additive inhibitory effects. Histologic evaluation of ankle joints demonstrated 68% or 25% inhibition of bone resorption with PEG sTNF-RI alone at 3.0 or 0.3 mg/kg. Treatment with 0.075, 0.06 or 0.045 mg/kg methotrexate resulted in 98%, 76% or 40% inhibition of bone resorption. Additive benefit was best seen with the lower doses of methotrexate. CONCLUSION: Combination therapy with PEG sTNF-RI and methotrexate results in additive benefit, with the final result being excellent inhibition of all arthritis parameters. Data from these studies supports the clinical investigation of the use of combination therapy of PEG sTNF-RI and methotrexate in rheumatoid arthritis patients.

Animals↗

Outcome and racing performance after internal fixation of third and central tarsal bone slab fractures in horses. A review of 20 cases.

Twenty horses with central and third tarsal bone slab fractures, were treated internal fixation. Eighteen of the 20 cases were Standardbred trotters, one was a Thoroughbred racehorse and one a Swedish Warmblood. The central tarsal bone (CT) was involved in 12 cases and the third tarsal bone (T3) in 8 cases. The fractures were treated by lag screw fixation with one (18 cases) or two (2 cases) 3.5 or 4.5 mm cortical screws. Horses were confined to stall rest for one month and then put on a gradually increasing exercise programme. Convalescence time was 3-8 months until the fracture had healed and training could be resumed. Fifteen of the horses regained athletic soundness. Thirteen of the horses (72%) raced after surgery (12 Standardbreds and 1 Thoroughbred). Nine (69%) of these 13 horses won races after surgery.

Animals↗

Taxol (paclitaxel) involution of articular cartilage destruction in collagen induced arthritis: an ultrastructural demonstration of an increased superficial chondroprotective layer.

OBJECTIVE: To determine the ultastructural changes of Taxol (paclitaxel) involution of articular cartilage destruction in collagen induced arthritis (CIA) and to compare with articular cartilage from normal rats. METHODS: Forty-five Louvain rats were randomized to one of 3 protocols for structural analysis: (1) control group, (2) CIA group, and (3) Taxol treated CIA group. The latter group received 10 mg/kg body weight of Taxol at Days 10, 12, and 14 and 7.5 mg/kg body weight of Taxol on Days 16, 18, and 20 postimmunization with collagen type II. Eight days later, each group was examined by light microscopy and scanning and transmission electron microscopy. RESULTS: In Taxol treated rats, the morphology of the articular cartilage reverted to that observed in naive rats except for a striking increase in the thickness of the superficial amorphous layer covering the articular surface. CONCLUSION: The involution of CIA by Taxol suggests that this agent may be useful in the clinical treatment of RA.

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"Osmetrichia" in the grey brocket deer (Mazama gouazoubira).

Osmetrichia have been defined as hairs specialized in the storage of secretions used in olfactory communication between conspecifics (Müller-Schwarze, et al. 1977). These authors found highly specialized osmetrichia in the tarsal gland tufts of black-tailed but not white-tailed deer. Chemical communication appears to be well developed in grey brocket deer: the bucks scent mark by rubbing their foreheads on bushes, and all deer urinate and defecate almost exclusively on dung heaps. Brocket deer also possess tarsal tufts. The purpose of this study was to examine hairs from several glandular areas in this species. Osmetrichia, similar to those found in black tailed deer, were found in tarsal tufts and in interdigital gland hairs; these hairs possessed open scales with deep pockets suitable for holding secretions, in comparison to the flat scales seen on control hairs. Hairs with different morphological characteristics (slightly open scales) were found over the frontal gland. Specialized hairs were not found in the tarsal tufts of one specimen of a related species, the red brocket deer (Mazama americana). The similarities in the hairs of grey brocket and black-tailed deer are remarkable in light of the ecological and behavioral differences between these two species.

Animals↗

[The syndrome of external ligament sprain in the horse].

The treatment of acute complete (grade III) tears of the lateral ligaments of the ankle has generated much controversy in the medical literature. Functional treatment has become the standard treatment as it has been shown that there is no significant difference in long term results whatever the treatment (operative repair and cast, cast alone, or early controlled mobilization). Functional treatment includes only a short period of protection by tape bandage or brace and allows early weight-bearing. Major trauma with avulsion of bone and severe ligamentous damage on both medial and lateral sides of the ankle is however an indication for surgical treatment in the acute phase. Secondary operative reconstruction can be performed in case of persistent instability and laxity of the ankle. Secondary anatomic repair as proposed by Brodström, Duquennoy et al. and Karlsson et al. has a high rate of success and avoids the potential morbidity of harvesting partially or totally the peroneus brevis or other tendon grafts. Evaluation of the injured ankle has improved and in selected patients ultrasonography, arthrography, magnetic resonance imaging or bone scintigraphy may be useful for further evaluation of the injury. The frequency of associated injuries has probably been underestimated. Although ankle sprain is often thought of as an injury involving only the lateral ankle ligaments, there are varied and multiple components to the common sprained ankle. This condition would perhaps more appropriately be designated as the sprained ankle syndrome.

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Iontophoresis of dexamethosone-phosphate into the equine tibiotarsal joint.

In human rehabilitation medicine, dexamethasone-phosphate is theoretically iontophoresed to localized subcutaneous tissue where conversion to dexamethasone occurs. This delivery system has recently been introduced into veterinary medicine for the same purpose. However, the pharmacokinetic justification for parenteral delivery of this prodrug remains undocumented. Utilizing iontophoretic methods that are relevant to both human and veterinary clinical practice, the present investigation compared injection and iontophoresis of dexamethasone-phosphate into the equine tibiotarsal joint, also known as the tarsocrual joint. The tibiotarsal joints of seven horses were injected with 4 mL of 6 mg/mL dexamethasone-phosphate. With a similar drug concentration and over the same application site, six different horses underwent simultaneous cathodic iontophoresis (4 mA, 40 min) or passive application (0 mA, 40 min) on contralateral limbs. Following all applications, tibiotarsal joint synovium was collected. Local venous blood samples were also collected from the iontophoretic and passive application sites for analysis of plasma drug concentrations. Because of the potential for conversion of dexamethasone-phosphate to dexamethasone, an extraction and analysis protocol was developed for both chemicals. The technique demonstrated a linear range of detection (0.39-12 microg/mL) and a capability for measuring both chemicals in plasma and synovium. Conversion of dexamethasone-phosphate to dexamethasone occurred during synovial incubation (37 degrees C) and following freeze-thaw cycles. In contrast to the measurable synovial concentrations of dexamethasone-phosphate (2.3 +/- 0.96 mg/mL) and dexamethasone (0.27 +/- 0.07 mg/mL) following injection, neither drug was detected in the synovium or the local venous blood following iontophoretic or passive applications. In conclusion, these results do not confirm iontophoretic or passive delivery of measurable dexamethasone-phosphate into the tibiotarsal joint using current clinical methods.

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