Multiparameter Phospho-Flow Analysis of Lymphocytes in Early Rheumatoid Arthritis: Implications for Diagnosis and Monitoring Drug Therapy

The precise mechanisms involved in the initiation and progression of rheumatoid arthritis (RA) are not known. Early stages of RA often have non-specific symptoms, delaying diagnosis and therapy. Additionally, there are currently no established means to predict clinical responsiveness to therapy. Immune cell activation is a critical component therefore we examined the cellular activation of peripheral blood mononuclear cells (PBMCs) in the early stages of RA, in order to develop a novel diagnostic modality.PBMCs were isolated from individuals diagnosed with early RA (ERA) (n = 38), longstanding RA (n = 10), osteoarthritis (OA) (n = 19) and from healthy individuals (n = 10). PBMCs were examined for activation of 15 signaling effectors, using phosphorylation status as a measure of activation in immunophenotyped cells, by flow cytometry (phospho-flow). CD3+CD4+, CD3+CD8+ and CD20+ cells isolated from patients with ERA, RA and OA exhibited activation of multiple phospho-epitopes. ERA patient PBMCs showed a bias towards phosphorylation-activation in the CD4+ and CD20+ compartments compared to OA PBMCs, where phospho-activation was primarily observed in CD8+ cells. The ratio of phospho (p)-AKT/p-p38 was significantly elevated in patients with ERA and may have diagnostic potential. The mean fluorescent intensity (MFI) levels for p-AKT and p-H3 in CD4+, CD8+ and CD20+ T cells correlated directly with physician global assessment scores (MDGA) and DAS (disease activity score). Stratification by medications revealed that patients receiving leflunomide, systemic steroids or anti-TNF therapy had significant reductions in phospho-specific activation compared with patients not receiving these therapies. Correlative trends between medication-associated reductions in the levels of phosphorylation of specific signaling effectors and lower disease activity were observed.Phospho-flow analysis identified phosphorylation-activation of specific signaling effectors in the PB from patients with ERA. Notably, phosphorylation of these signaling effectors did not distinguish ERA from late RA, suggesting that the activation status of discrete cell populations is already established early in disease. However, when the ratio of MFI values for p-AKT and p-p38 is >1.5, there is a high likelihood of having a diagnosis of RA. Our results suggest that longitudinal sampling of patients undergoing therapy may result in phospho-signatures that are predictive of drug responsiveness

Contact dermatitis and other skin conditions in instrumental musicians

BACKGROUND: The skin is important in the positioning and playing of a musical instrument. During practicing and performing there is a permanent more or less intense contact between the instrument and the musician's skin. Apart from aggravation of predisposed skin diseases (e.g., atopic eczema or psoriasis) due to music-making, specific dermatologic conditions may develop that are directly caused by playing a musical instrument. METHODS: To perform a systematic review on instrument-related skin diseases in musicians we searched the PubMed database without time limits. Furthermore we studied the online bibliography "Occupational diseases of performing artist. A performing arts medicine bibliography. October, 2003" and checked references of all selected articles for relevant papers. RESULTS: The most prevalent skin disorders of instrumental musicians, in particular string instrumentalists (e.g., violinists, cellists, guitarists), woodwind players (e.g., flautists, clarinetists), and brass instrumentalists (e.g., trumpeters), include a variety of allergic contact sensitizations (e.g., colophony, nickel, and exotic woods) and irritant (physical-chemical noxae) skin conditions whose clinical presentation and localization are usually specific for the instrument used (e.g., "fiddler's neck", "cellist's chest", "guitar nipple", "flautist's chin"). Apart from common callosities and "occupational marks" (e.g., "Garrod's pads") more or less severe skin injuries may occur in musical instrumentalists, in particular acute and chronic wounds including their complications. Skin infections such as herpes labialis seem to be a more common skin problem in woodwind and brass instrumentalists. CONCLUSIONS: Skin conditions may be a significant problem not only in professional instrumentalists, but also in musicians of all ages and ability. Although not life threatening they may lead to impaired performance and occupational hazard. Unfortunately, epidemiological investigations have exclusively been performed on orchestra musicians, though the prevalence of instrument-related skin conditions in other musician groups (e.g., jazz and rock musicians) is also of interest. The practicing clinician should be aware of the special dermatologic problems unique to the musical instrumentalist. Moreover awareness among musicians needs to be raised, as proper technique and conditioning may help to prevent affection of performance and occupational impairment

Shoulder joint contact force during lever-propelled wheelchair propulsion

The aim of this study was to obtain quantitative results about shoulder contact force during wheelchair lever propulsion when the gear ratio of the lever propulsion mechanism is changing. The effect of the gear ratio on the shoulder contact force was investigated for few different wheelchair loading. For the experiments we designed a special mechatronic wheelchair simulator that allowed the simulation of different gear ratios ofthe wheelchair lever propulsion mechanism and simulation of different road inclinations. The same simulator was also used for simulation of a hand rim propelled wheelchair. We conducted also a hand rim propulsion experiment and used the results from it for comparison with the lever propulsion data. Four nondisabled male adults with no prior wheeling experience participated in the experiment. In the first tests, a lever propelled wheelchair was simulated with the simulator. The target speed of the wheelchair was set to 2 km/h. For the test the gear ratio was varied from 1.5 to 1/1.5. A load torque was applied to the rear wheels to imitate road inclinations of 0, 2° and 4°.ln the second part of the test, the simulator was structured to simulate a hand rim propelled wheelchair. The participants were asked to keep the same speed (2 km/h) and the simulator was set sequentially to imitate climbing a ramp inclined on 0°,2° and 4°. Kinematic data of the body were collected by a motion capture system. Kinetic data such as hand force and driving torque, were measured by instrumented wheels with incorporated six-axis force sensor. The intersegmental joint forces and moments were calculated from the obtained kinematic and kinetic data via inverse dynamics analysis procedure. Muscle forces were computed from the measured joint moments by using an optimization approach. Shoulder joint contact force, which indicates the joint surface loading, was computed as a synthetic vector of the intersegmental force for shoulder joint acquired from the inverse dynamics analysis and the compressive forces from muscles, tendons, ligaments and cartilages crossing the shoulder joint It was observed that the decrease of the gear ratio causes increased cycle frequency and reduces the shoulder joint contact force. Result showed that the shoulder joint contact force during lever propulsion with a gear ratio 1/1.5 was up to 70% lower than the shoulder joint contact force during handrim propulsion. The results from this study could be used in the design of new lever propulsion mechanisms that reduce the risks of secondary shoulder disorders and increase user's comfort