Proteoglycan synthesis and osteophyte formation in 'metabolically' and 'mechanically' induced murine degenerative joint disease: an in-vivo autoradiographic study.

We investigated the in-vivo proteoglycan synthesis in specific areas of murine knee joint articular cartilage after the induction of degenerative joint disease by means of 35S-sulphate autoradiography. Degenerative joint disease was induced either by direct interference with cartilage metabolism (papain and iodoacetate), or by the induction of joint instability (collagenase). Injection of iodoacetate and papain led to inhibition of proteoglycan synthesis mainly in the central parts of the patellae, patellaris femoris and the central part of the medial tibial plateau. Articular cartilage adjacent to the strongly inhibited areas frequently showed a significantly enhanced synthesis of proteoglycans. A strong inhibition of proteoglycan synthesis was observed in the central part of the medial plateau after collagenase injection while other cartilage sites and joint structures such as the capsule and ligaments were stimulated in their proteoglycan synthesis. This study shows that the localization of changes in cartilage metabolism in degenerative joint disease of the knee might be related to differences in the pathogenetic mechanism in different variants of this common joint disorder.     

Induction of osteoarthritis by intra-articular injection of collagenase in mice. Strain and sex related differences

To study the effects of strain and sex on the development of injury-induced osteoarthritis (OA) in murine knee joints, two doses of highly purified bacterial collagenase (10 units and 30 units) were injected into male and female mice of two closely related strains, C57BL6 and C57BL10. Frontal histological sections of whole knee joints were made late in the disease process and examined for osteoarthritic lesions. Differences in prevalence of cartilage damage between strains and sexes were observed. Prevalence was higher in C57BL10 (male: almost 100%) than in C57BL6 (male: about 25%), and the prevalence was twice as high in males as in females in both strains. The amount of collagenase (10 or 30 units) did not affect the prevalence of lesions, however, it did influence the severity of the damage. The site of the damage appeared to be dose and strain dependent. Male C57BL6 always showed damage on the medial tibial plateau, independent of dose. In male C57BL10 damage almost always appeared on the lateral tibial plateau with 10 units, while with 30 units the medial plateau also became strongly involved. Since it is known that male mice are more prone to spontaneous OA than female mice and C57BL10 are more prone han C57BL6 mice, it can be concluded that predisposition to spontaneous osteoarthritis increases the risk of developing injury-induced osteoarthritis. Location and severity of the changes will probably be related to joint loading.     

High susceptibility of human articular cartilage glycosaminoglycan synthesis to changes in inorganic sulfate availability

The effect of sulfate concentration in the medium on glycosaminoglycan synthesis in articular cartilage of five different species was examined in relation to the physiological serum sulfate concentration in these species. Only the rate of sulfated glycosaminoglycan synthesis in human articular cartilage was sensitive to small deviations from the physiological sulfate concentration. A reduction in the sulfate concentration from 0.3 mM (physiological) to 0.2 mM resulted in a 33% reduction in glycosaminoglycan synthesis. In addition, we studied the effect of arthritic and "osteoarthritic" alterations in murine cartilage on the dependence of glycosaminoglycan synthesis on low sulfate concentrations. Arthritic and "osteoarthritic" cartilage had a similar dependence on the sulfate concentration in the medium as normal cartilage. Glycosaminoglycan synthesis in human articular cartilage appears to be very sensitive to the potential sulfate-depleting effects of drugs used in the treatment of rheumatoid arthritis and osteoarthritis.     

Imbalances in circulating lymphocyte subsets in Hu antibody associated paraneoplastic neurological syndromes

In paraneoplastic neurological syndromes (PNS) associated with small cell lung cancer (SCLC) and Hu antibodies, neuron-specific Hu antigens expressed by the tumour hypothetically trigger an immune response that cross-reacts with Hu antigens in the nervous system, resulting in tumour suppression and neuronal damage. To gain more insight into the hypothesized cell-mediated immune pathogenesis of these syndromes, we analysed the circulating lymphocyte subsets in untreated patients with SCLC, PNS and Hu antibodies ( n  = 18), SCLC without PNS ( n  = 19) and controls ( n  = 29) using flow cytometry. SCLC patients with PNS had a variety of imbalances within their circulating lymphocyte subsets as compared with SCLC patients without PNS and healthy controls: (i) a lymphopenia of the major subsets (i.e. B, CD4⁺ and CD8⁺ T lymphocytes); (ii) increased proportions of activated CD4⁺ and CD8⁺ T cells; (iii) reduced numbers of terminally differentiated effector CD8⁺ T cells and cells with a cytotoxic T-cell phenotype (CD56⁺ and CD57⁺). Although indirect, our data provide further support for the involvement of T cells in the pathogenesis of Hu antibody associated PNS.     

Long-term follow-up of distal radius fractures,an evaluation of the current guideline: the relation between malunion,osteoarthritis and functional outcome

European Journal of Orthopaedic Surgery & Traumatology - Last decades there is an increased tendency of performing surgery on displaced distal radius fractures. However, it is unclear whether...     

Dosage and time effects of inhaled budesonide on bronchial hyperreactivity

In a double-blind study of 2 parallel groups of 15 allergic asthmatic patients each, we investigated whether treatment with inhaled budesonide has a dose- and time-dependent effect on the degree of bronchial hyperreactivity. The patients were randomly allocated to treatment with either 200 or 800 micrograms budesonide per day for a period of 8 wk. The active treatment period was preceded by a selection period of 3 wk, and a single-blind placebo period of 2 wk. During these initial 5 wk the maintenance treatment of the patients, including cromolyn sodium and inhaled corticosteroids, was withheld. Spirometry and inhalation provocation tests with methacholine were carried out, and the symptom score was recorded every 2 wk. The methacholine provocation concentrations (geometric mean) causing a decrease in FEV1 of 20% (PC20) in the 200 and 800 micrograms/day treatment groups just before the active treatment period were 0.90 and 0.91 mg/ml, respectively. These values increased significantly to 1.21 and 1.84 mg/ml after 2 wk of treatment (p less than 0.05 and p less than 0.001, respectively) and to 1.55 and 2.74 mg/ml after 8 wk of treatment (p less than 0.01 and p less than 0.001). During the whole study period budesonide in a dosage of 800 micrograms/day induced a significantly larger change in PC20 than in a dosage of 200 micrograms/day. The FEV1 before treatment was 91 +/- 3% (SEM) and 84 +/- 2% of the predicted value in the 200 and 800 micrograms/day treatment groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of leflunomide and methotrexate on cytokine production in rheumatoid arthritis

BACKGROUND: T cells have a pivotal role in RA. Leflunomide inhibits pyrimidine biosynthesis, to which T cells are especially susceptible, and therefore may have a different cytokine profile than methotrexate. MATERIALS AND METHODS: Serum samples of 100 patients with RA, treated with leflunomide (n = 50) or methotrexate (n = 50), were collected at baseline, after 16 weeks and after 1 year's treatment. Serum levels of interleukin 6 (IL6), and interferon (IFN) gamma were determined by ELISA. Additionally, peripheral blood mononuclear cells (PBMC) of five healthy volunteers and three patients with RA were isolated and the effects of the active metabolite of leflunomide (A77-1726, 0-200 mmol/l) on cell proliferation and on IL6 and IFNgamma production were determined by ELISA. In peripheral blood lymphocytes (PBL) and monocytes (PBM) from two healthy volunteers the effects of A77-1726 on IL6 production were measured by ELISA and PCR. RESULTS: Mean (SEM) serum levels of IFNgamma were significantly reduced after leflunomide treatment (baseline 43 (10) pg/ml; 1 year 29 (7) (p = 0.015), but there was no change in IL6 levels (baseline 158 (41), 1 year 151 (48)). Both IFNgamma and IL6 levels were significantly reduced after methotrexate treatment. This observation was supported by in vitro experiments. The production of IFNgamma by PBL was inhibited by A77-1726, but IL6 production by PBM was not inhibited. CONCLUSION: The differential effect on IFNgamma and IL6 production supports the hypothesis that activated T cells are preferentially inhibited by leflunomide. An explanation may be either inhibition of uridine synthesis or effects on signal transduction pathways.