Limb development in mouse embryos: protection against teratogenic effects of 6-diazo-5-ox-L-norleucine (DON) in vivo and in vitro.
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The glutamine analogue, 6-diazo-5-oxo-L-norleucine (DON), has been shown to inhibit biosynthesis of purines and glycosaminoglycans, presumably by blocking the glutamine-dependent steps in the biosynthetic pathways. The teratogenic potential of DON on the developing mouse limb-bud in vivo and in vitro was studies in an attempt to discriminate whether DON is exerting its teratogenic effect by interfering with glycosaminoglycan or purine metabolism. A single intramuscular injection of DON (0-5 mg/kg) to ICR/DUB mice on day 10 of gestation resulted in 76% resorption, while fetuses surviving to day 17 exhibited growth retardation, median cleft lip, and limb malformation. Concurrent administration of L-glutamine (250 mg/kg) provided no protection against resorption of malformations, while 5-aminoimidazolecarboxamide (AIC, 250 mg/kg) decreased the resorption rate to 34% without significantly altering the incidence of malformations. Injection of DON alone on day 11 resulted in 87% of fetuses exhibiting limb formations, with only 2% resorption. Concurrent injection of AIC decreased the frequency of limb malformations to 32% L-Glutamine, D-glucosamine, or inosinic acid were without any protective effect in vivo. DON (5mug/ml medium) added in vitro to organ cultures of day 11 mouse limb-buds caused all limbs to evidence cartilage abnormalities. In this system, either L-glutamine ro D-glucosamine (0-5 mg/ml medium) provided protection against DON effects while AIC (0-5 mg/ml medium) offered no protection in vitro. These data suggest that DON exerts its effects in vivo by interfering with purine metabolism while in vitro its teratogenic action may be interruption of glycosaminoglycan biosynthesis. This may reflect upon the relative importance of growth and differentiation to limb development in vivo and in vitro. These data infer that limb development in vitro relies more on the differentiative process (differentiation of cartilage) than on growth, whereas limb development in vivo is dependent, at this stage, to a greater extent on growth for normal phenotypic expression. (+info)
The effect of bone remodeling inhibition by zoledronic acid in an animal model of cartilage matrix damage.
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OBJECTIVE: The purpose of this work was to test the effect of inhibition of bone remodeling, through the use of the bisphosphonate, zoledronic acid, on cartilage matrix damage in an animal model of cartilage matrix damage. DESIGN: New Zealand white rabbits were divided into four groups for treatment purposes: (1) untreated controls; (2) injected into one knee joint with the cartilage matrix degradation enzyme, chymopapain; (3) injected into one knee joint with chymopapain and also given subcutaneous injections of the bisphosphonate, zoledronic acid, three times per week until sacrifice at either day 28 or 56 post-chymopapain-injection; (4) received only the zoledronic acid injections. At sacrifice, the knee joints were examined grossly and histologically, and biochemically for proteoglycan content. Urine samples were analysed, at intervals, for levels of collagen cross-links which are biochemical markers of cartilage and bone. RESULTS: Animals receiving both intraarticular chymopapain injections and subcutaneous zoledronic acid injections displayed a significantly lower degree of grossly and histologically detectable cartilage degeneration on the tibial articular surfaces (the articular surface displaying the greatest degree of degeneration) than did animals only receiving the chymopapain injections. In addition, urinary levels of collagen cross-links for bone and cartilage were significantly higher in those animals only receiving chymopapain injections. CONCLUSION: The bone resorption observed after chymopapain injection into the rabbit knee joint can be inhibited through the use of the bisphosphonate, zoledronic acid. Furthermore, zoledronic acid does not increase the level of cartilage degeneration and appears to provide some level of chondroprotection in this model. (+info)
Poor accuracy and interobserver reliability of knee arthroscopy measurements are improved by the use of variable angle elongated probes.
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OBJECTIVES: (a)To determine the accuracy and reliability of arthroscopic measurements of cartilage lesion diameter in an artificial right knee model; (b) to determine whether the use of a set of variable angle elongated probes improves performance; and (c) to identify other sources of variability. METHODS: Ovoid "lesions" were drawn on the five cartilage surfaces of four plastic knees models. Two observers assessed these 20 lesions arthroscopically, measuring two diameters in orientations parallel and orthogonal to the probe. Observer 1 (orthopaedic surgeon) and observer 2 (arthroscopic rheumatologist) made two sets of measurements, firstly with the conventional probe and five months later with the variable angle elongated (VAE) probes. The knees were disarticulated to determine true lesion diameter. RESULTS: Observer 1 had negligible bias and good accuracy regardless of orientation or probe type. Observer 2 demonstrated both bias and poor accuracy using the conventional probe. Both improved using VAE probes. Poor interobserver reliability with conventional probes also improved using VAE probes. Major sources of variability could be traced to the probe type, the characteristics of the operator, and the orientation of the lesion in relation to the probe; the lesion location itself did not cause variability. CONCLUSIONS: Variation in accuracy and poor interobserver reliability of measurements with conventional methods of cartilage lesion diameter measurement improved when specially designed measurement probes were used. Arthroscopic measurements performed as well as most clinical and radiographic measures. These findings have important implications for the use of arthroscopy as an outcome in multicentre trials where arthroscopists have different levels of experience. (+info)
Synergistic effect of ofloxacin and magnesium deficiency on joint cartilage in immature rats.
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Single high oral doses of fluoroquinolones (e.g., 1,200 mg of ofloxacin/kg of body weight) are chondrotoxic in juvenile rats. Characteristic cartilage lesions are detectable as early as 12 h after treatment. Since this dosing regimen does not reflect the therapeutic situation, we studied the effects of a 5- or 7-day treatment with ofloxacin at lower oral doses (10, 30, and 100 mg/kg twice a day [b.i.d.]) on joint cartilage in 4-week-old rats. We additionally investigated whether the effects of ofloxacin under these conditions are enhanced in animals kept on a magnesium-deficient diet during treatment. Knee joints were examined histologically. The concentrations of ofloxacin and magnesium were determined in plasma and cartilage. The lowest ofloxacin dose at which cartilage lesions occurred in animals on a standard diet was 100 mg/kg b.i.d. for 5 days. Peak plasma ofloxacin levels were approximately 10 mg/liter in these rats and thus were in the same range as the levels in the plasma of humans during therapy with high doses of ofloxacin. Treatment with 30 mg of ofloxacin/kg b.i.d. for 7 days caused no cartilage lesions in rats on a standard diet, but lesions did occur in 10 of 12 rats that were simultaneously fed a magnesium-deficient diet. Magnesium concentrations in bone, plasma, and cartilage from animals on an Mg(2+)-deficient diet were significantly lower than those in the controls. The concentration in plasma from animals on an Mg(2+)-deficient diet was 0.27 +/- 0.03 mmol/liter, whereas it was 0.88 +/- 0.08 mmol/liter in plasma from rats on a standard diet (means +/- standard deviations). Ofloxacin treatment did not change the total magnesium concentrations in tissues, as determined with ashed samples. The incidence of ofloxacin-induced lesions was higher in the magnesium-deficient animals, suggesting a synergistic effect. These results must be taken into account for a benefit-risk evaluation if ofloxacin is considered for use in the pediatric population. (+info)
Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major70A-->G mutation of the untranslated RMRP.
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Pleiotropic, recessively inherited cartilage-hair hypoplasia (CHH) is due to mutations in the untranslated RMRP gene on chromosome 9p13-p12 encoding the RNA component of RNase MRP endoribonuclease. We describe 36 different mutations in this gene in 91 Finnish and 44 non-Finnish CHH families. Based on their nature and localisation, these mutations can be classified into three categories: mutations affecting the promoter region, small changes of conserved nucleotides in the transcript, and insertions and duplications in the 5' end of the transcript. The only known functional region that seemed to avoid mutations was a nucleolar localisation signal region between nucleotides 23-62. The most common mutation in CHH patients was a base substitution G for A at nucleotide 70. This mutation contributed 92% of the mutations in the Finnish CHH patients. Our results using linkage disequilibrium based maximum likelihood estimates with close markers, genealogical studies, and haplotype data suggested that the mutation was introduced to Finland some 3900-4800 years ago, and before the expansion of the population. The same major mutation accounted for 48% of the mutations among CHH patients from other parts of Europe, North and South America, the Near East, and Australia. In the non-Finnish CHH families, the A70G mutation segregated with the same major haplotype, although shorter, as in most of the Finnish families. In 23 out of these 27 chromosomes, the common region extended over 60 kb, and, therefore, all the chromosomes most likely arose from a solitary event many thousands of years ago. (+info)
Effects of the Des-F(6)-quinolone garenoxacin (BMS-284756), in comparison to those of ciprofloxacin and ofloxacin, on joint cartilage in immature rats.
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We did not observe signs of chondrotoxicity in immature rats treated orally with garenoxacin (BMS-284756) at doses up to five times 600 mg/kg of body weight or with ciprofloxacin, whereas ofloxacin induced typical cartilage lesions. The peak plasma garenoxacin concentration was 25.5 mg/liter after administration of a dose of 600 mg/kg once daily for 5 days. Assuming that this model is predictive of human risk, BMS-284756 and ciprofloxacin should be more suitable for pediatric use than ofloxacin. (+info)
Increased serum cartilage oligomeric matrix protein levels and decreased patellar bone mineral density in patients with chondromalacia patellae.
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BACKGROUND: Chondromalacia patellae is a potentially disabling disorder characterised by features of patellar cartilage degradation. OBJECTIVE: To evaluate markers of cartilage and bone turnover in patients with chondromalacia patellae. METHODS: 18 patients with chondromalacia patellae were studied. Serum cartilage oligomeric matrix protein (s-COMP) and bone sialoprotein (s-BSP) levels were measured by enzyme linked immunosorbent assay (ELISA) and compared with those of age and sex matched healthy control subjects. Periarticular bone mineral density (BMD) of both knee joints was assessed by dual energy x ray absorptiometry (DXA). RESULTS: s-COMP levels were significantly raised in all patients with chondromalacia patellae compared with healthy control subjects (p=0.0001). s-BSP levels did not differ significantly between the groups (p=0.41). BMD of the patella was significantly reduced in patients with chondromalacia patellae compared with the control subjects (p=0.016). In patients with bilateral chondromalacia patellae, BMD of the patella was lower in the more symptomatic knee joint (p=0.005). Changes in periarticular BMD were localised to the patella and were not present in femoral regions. Neither s-COMP (p=0.18) nor s-BSP (p=0.40) levels correlated with patellar BMD. CONCLUSIONS: Increased s-COMP levels, reflecting cartilage degradation, and reduced BMD localised to the patella may represent clinically useful markers in the diagnosis and monitoring of patients with chondromalacia patellae. Measures of cartilage degradation did not correlate with loss of patellar bone density, suggesting dissociated pathophysiological mechanisms. (+info)
Visceral nodular cartilaginous metaplasia in rockfishes (Sebastes spp.) in the eastern North Pacific Ocean.
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Multiple, discrete, nodular foci of cartilaginous metaplasia were found in the spleens and kidneys of rockfishes taken from the northeastern Pacific Ocean during a survey to determine the incidence and the nature of diseases in these animals. These nodules sometimes occurred in association with granulomatous inflammation and distinct granulomas. Many of these fish were infected by Ichythophonus spp. or acid-fact bacteria (presumably Mycobacteria spp.). Some of the metaplastic foci contained encapsulated accumulations of eosinophilic vesicles and basophilic granular debris, described by other authors as "cysts of unknown etiology," which have been observed at different sites in a variety of temperate and tropical fish species. (+info)