Age-related changes in arthritis susceptibility and severity in a murine model of rheumatoid arthritis

Background

Rheumatoid arthritis (RA) most often begins in females in the fourth-fifth decade of their life, suggesting that the aging of the immune system (immunosenescence) has a major role in this disease. Therefore, in the present study, we sought to investigate the effect of age on arthritis susceptibility in BALB/c mice using the proteoglycan (PG)-induced arthritis (PGIA) model of RA.

Results

We have found that young, 1-month-old female BALB/c mice are resistant to the induction of PGIA, but with aging they become susceptible. PG-induced T cell responses decline with age, whereas there is a shift toward Th1 cytokines. An age-dependent decrease in T cell number is associated with an increased ratio of the memory phenotype, and lower CD28 expression. Antigen-presenting cells shifted from macrophages and myeloid dendritic cells in young mice toward B cells in older mice. The regulatory/activated T cell ratio decreases in older mice after PG injections indicating impaired regulation of the immune response.

Conclusion

We conclude that immunosenescence could alter arthritis susceptibility in a very complex manner including both adaptive and innate immunities, and it cannot be determined by a single trait. Cumulative alterations in immunoregulatory functions closely resemble human disease, which makes this systemic autoimmune arthritis model of RA even more valuable.     

Cough reflex changes in local tracheitis.

The authors describe changes in the cough reflex in unanaesthetized cats with experimental local tracheitis. Inflammation was produced by a silk suture fixed in the trachea and cough was elicited by mechanical stimulation of different parts of the respiratory tract mucosa. The resultant cough values (the number of efforts, the intensity of the maximum effort and the intensity of the attack) were compared with the corresponding values in healthy cats. In animals with a tracheal suture, inflammation was confined to the trachea. The intensity of cough elicited by stimulation of this region increased significantly compared with normal (on the 15th to 17th day of inflammation), whereas cough elicited from the laryngopharyngeal and tracheobronchial region did not. On about the 20th day of inflammation the authors found a decrease in the intensity of the maximum effort of cough elicited from the inflamed part of the trachea and a decrease in the intensity of the maximum effort and the intensity of the coughing attack elicited from the laryngopharyngeal and tracheobronchial region. They assume that the decrease could have been due to the development of protective inhibition in central structures participating in integration of the cough reflex.     

Gait changes precede overt arthritis and strongly correlate with symptoms and histopathological events in pristane-induced arthritis

Introduction  

Pristane-induced arthritis (PIA) in the rat has been described as an animal model of inflammatory arthritis which exhibits features similar to rheumatoid arthritis in humans, such as a chronic, destructive, and symmetrical involvement of peripheral joints. However, so far little is known about the earliest inflammatory events and their influence on locomotor behaviour during the course of PIA. To investigate this issue a detailed analysis of the pathologic changes occurring during the prodromal and early stages of PIA was performed.     

Drug-induced changes in chemotaxis under normal conditions and in rheumatoid arthritis

The effects of agents used in RA treatment, various drugs, RF, rheumatoid nodule and synovial fluid was studied on chemotaxis of PMNs. NSAIDS, corticosteroids, theophylline, colchicine, SOD, RF, rheumatoid nodule and synovial fluid were found to inhibit the chemotactic responsiveness while AMPc, GMPc, PGEI and immunodulator drugs enhanced chemotaxis. The results support the hypothesis that drugs tested may modulate chemotactic function by affecting cellular microtubules assembly and/or GMPc accumulation.     

X-ray characterization of changes of the lungs in juvenile rheumatoid arthritis

The results of chest x-ray were analyzed in 66 pediatric patients with juvenile rheumatoid arthritis (JRA). X-ray signs of pneumofibrosis were revealed in 37 (56%) patients. Besides, rare pulmonary changes (emphysema, rheumatic nodules, infiltrates) were detected in the JRA patients. The absence of clinical symptoms in the presence of x-ray changes necessitates the performance of chest x-ray in JRA for early detection of the pulmonary symptoms of this disease.     

Morphofunctional changes in the microcirculatory bed of the synovial membrane in antigen-induced arthritis

Ultrastructural changes of synovial capillary and venule wall have been investigated in rabbits with antigen-induced arthritis, with the permeability of microcirculatory bed determined using 99mTc pertechnetate. The correlation between the incidence of ultrastructural microvascular damages in exudative phase of arthritis and the increased permeability has been established. Ultrastructural changes occurring in proliferative phase of arthritis are considered as adaptive to conditions of increased permeability.     

Finger and forearm vasodilatatory changes after local cold acclimation

To determine the vascular changes induced by local cold acclimation, post-ischaemia and exercise vasodilatation were studied in the finger and the forearm of five subjects cold-acclimated locally and five non-acclimated subjects. Peak blood flow was measured by venous occlusion plethysmography after 5 min of arterial occlusion (PBFisc), after 5 min of sustained handgrip at 10% maximal voluntary contraction (PBFexe), and after 5 min of both treatments simultaneously (PBFisc + exe). Each test was performed at room temperature (25 degrees C, SE 1 C) (non-cooled condition) and after 5 min of 5 degrees C cold water immersion (cooled condition). After the cold acclimation period, the decrease in skin temperature was more limited in the cold-acclimated compared to the non-acclimated (P less than 0.01). The PBFisc was significantly reduced in the cooled condition only in the cold-acclimated subjects (finger: 8.4 ml.100 ml-1.min-1, SE 1.1, P less than 0.01; forearm: 5.8 ml.100 ml-1.min-1, SE 1.5, P less than 0.01) compared to the non-cooled condition. Forearm PBFexe was significantly decreased in the cooled condition only in the cold-acclimated subjects (non-cooled: 7.4 ml.100 ml-1.min-1, SE 1.2; cooled: 3.9 ml.100 ml-1.min-1, SE 2.6, P less than 0.05) indicating that muscle blood flow was also reduced.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phase-dependent changes in local dynamic stability of human gait

Several methods derived from nonlinear time series analysis have been suggested to quantify stability in human gait kinematics. One of these methods is the definition of the maximum finite time Lyapunov exponent (λ) that quantifies how the system responds to infinitesimal perturbations. However, there are fundamental limitations to the conventional definition of λ for gait kinematics. First, exponential increase in initial perturbations cannot be assumed since real-life perturbations of gait kinematics are finite sized. Second, the transitions between single and double support phase within each stride cycle define two distinct dynamical regimes that may not be captured by a single λ. The present article presents a new method to quantify intra-stride changes λ(t) in local dynamical stability and employs the method to 3D lower extremity gait kinematics in 10 healthy adults walking on a treadmill at 3 different speeds. All participants showed an intra-stride change in λ(t) in the transition between single and double support phase. The intra-stride change reflected an both a increase and decrease in λ(t) at heel strike and toe off, respectively, with increased gait speed. Furthermore, a close relationship was found between the intra-stride change in standard deviation of foot velocity in the anterior-posterior direction and the intra-stride change of the initial perturbations. The present results indicate that local dynamical stability has gait phase-dependent changes that are not identified by conventional computation of a single λ.     

Relations of the EEG local and spatialtemporal spectral characteristics changes under hypoxia in humans

Spatial temporal and local EEG characteristics were studied in healthy subjects during inhalation of hypoxic oxygen-nitrogen gas mixture with 8 % content of oxygen. Analysis of spectra power density, coherence, phase shift, similarity of dominant frequencies in the EEGs of different derivations was performed separately for the EEG epochs with and without visually detected patterns of spatial synchrony of the EEG. Apart from this, a fact of dominance of the frequency in the EEG spectra of corresponding derivation was taken into account when estimating spectral parameters. Results of the study showed that, in general, under hypoxia, the EEG coherence in alpha- and delta-frequency range decreases as compared to the background level, in beta-range growth of this parameter is observed, in theta-range ambiguous changes occur: in the epochs with patterns of spatial synchrony--growth, in other epochs--lowering. Under hypoxia, also occurs growth of frontal and temporal EEGs' phase shift (corresponding to EEGs other derivations) in delta- and theta-range. In beta-range, on the contrary, average level of the phase shift decreases. It was revealed that taking into account the fact of dominance of frequency in the local EEG spectra is necessary for correct interpretation of the EEG spatial and temporal parameter analysis' results. A mathematical model of interaction between processes with different frequency characteristics is suggested, which explains some facts obtained in the study.     

Modification of the adjuvans arthritis by carrageenin, compound 48/80, histamine- and serotonin antagonists, non-steroid antiphlogistics as well as protease inhibitors and their possible relations to inflammation mediators]

1. Injections of carrageenin (1,25 mg/kg i.v.) from the 1st to the 3rd day and then each 2nd or 3rd day inhibited paw swelling in adjuvant arthritis of the rat during the time of treatment. Injections from the 11th to the 15th day were ineffective. The level of plasma kininogen was slightly decreased but the total complement serum level was significantly lowered. 2,5 and 3 mg carrageenin/kg respectively were toxic after repeated injections. After a single administration the levels of plasma kininogen and of total serum complement were decreased by 50% although paw swelling was not affected. 2. Pentosane polysulfoester (25 mg/kg i.v.) did not influence paw swelling despite daily administration from the 1st to the 17th day. Heparin (10 000 IE/kg i.v.) was likewise ineffective. 3. Single or repeated injections of compound 48/80 (0,125-0,5 mg/kg i.v.; 1-5 mg/kg i.p.; 3-6 mg/kg s.c.), reserpine (0,2 mg/kg i.p.), cyproheptadine (5 mg/kg i.v.), bromolysergic acid diethylamide (2 x 2 mg/kg i.v.) or metiamide (10 mg/kg i.v.) were without effect on paw swelling. Neither did compound 48/80 effect the complement serum level. 4. Daily administration of chloropromazine (4-10 mg/kg p.o.) or of promethazine (10-15 mg/kg s.c. or p.o.) inhibited paw swelling in the first phase of adjuvant arthritis but not in the second one. 5. The soybean trypsin inhibitor (15 mg/kg i.v.) inhibited paw swelling significantly up to the 4th day, the Kunitz inhibitor (25 000 E/kg i.v.) was ineffective. 6. The content of prostaglandin E of the inflamed paws was increased threefold in both phases of arthritis. The results are discussed with regard to the putative role of mediators of inflammation (histamine, serotonin, kinins, prostaglandins, lysosomal enzymes, lymphokines, complement).     

Increased adiponectin is negatively linked to the local inflammatory process in patients with rheumatoid arthritis

Adiponectin has been shown to exert insulin-sensitizing, anti-atherogenic, and anti-inflammatory properties in metabolic diseases. It has been suggested that adiponectin may play a role in rheumatoid arthritis (RA). To assess adiponectin in serum and synovial fluid from patients with RA and osteoarthritis (OA), and in serum from healthy controls. Adiponectin and CRP levels were analyzed by ELISA. The clinical activity of RA patients was assessed according to the 28 joint count Disease Activity Score. Synovial fluid adiponectin was significantly higher in RA than in OA patients (p<0.001). Adiponectin was negatively associated with the leukocyte count in RA synovial fluid (r=-0.45, p<0.05). Serum adiponectin was higher in RA compared to healthy controls (p<0.02), however comparable to OA patients. Serum adiponectin was higher than in synovial fluid in both diseases (p<0.001). In general, women had higher adiponectin levels than men. Adiponectin was not related to age, disease duration, body mass index, or disease activity of RA patients. Adiponectin is decreased in synovial fluid compared to serum indicating that peripheral fat stores are major producers of adiponectin into the blood stream. However, increased synovial fluid adiponectin in RA patients may counterpart the local inflammatory process.     

Total body calcium in rheumatoid arthritis: effects of disease activity and corticosteroid treatment.

Rheumatoid arthritis may be associated with generalised as well as periarticular osteoporosis. To assess the extent of bone loss and the influence of corticosteroid treatment total body calcium was measured by in-vivo neutron activation analysis in 63 patients with rheumatoid arthritis treated with non-steroidal anti-inflammatory drugs alone and 31 treated with additional low-dose corticosteroids. The results were compared with those in 40 normal controls matched for age, sex, and menopausal state. There were significant reductions in mean total body calcium in the group treated with non-steroidal anti-inflammatory drugs (5.3% in men; 6.8% in women) and greater reductions in the corticosteroid-treated patients (11.5% in men, 15.5% in women). The reduction was correlated with disease duration and activity in the patients treated with non-steroid anti-inflammatory drugs alone. Measured total body calcium was significantly less than the values predicted when this relation was used in the corticosteroid-treated patients. The data suggest that increased bone loss in patients with rheumatoid arthritis treated with corticosteroids is attributable to drug treatment rather than disease activity. Many patients with rheumatoid arthritis treated with low-dosage corticosteroids and some postmenopausal women with the disease are likely to be at risk from the complications of osteoporosis.