Upper extremity tendinopathies are associated with performance of forceful repetitive tasks. We used our rat model of repetitive strain injury to study changes induced in forelimb flexor digitorum tendons. Rats were trained to perform a high repetition high force (HRHF) handle-pulling task (12 reaches/min at 60 AE 5% maximum pulling force [MPF]), or a low repetition negligible force (LRNF) reaching and food retrieval task (three reaches/min at 5 AE 5% MPF), for 2 h/day in 30 min sessions, 3 days/week for 3-12 weeks. Forelimb grip strength was tested. Flexor digitorum tendons were examined at midtendon at the level of the carpal tunnel for interleukin (IL)-1b, neutrophil, and macrophage influx, Substance P, connective tissue growth factor (CTGF), and periostin-like factor (PLF) immunoexpression, and histopathological changes. In HRHF rats, grip strength progressively decreased, while IL-1b levels progressively increased in the flexor digitorum peritendon (para-and epitendon combined) and endotendon with task performance. Macrophage invasion was evident in week 6 and 12 HRHF peritendon but not endotendon. Also in HRHF rats, Substance P immunoexpression increased in week 12 peritendon as did CTGF-and PLF-immunopositive fibroblasts, the increased fibroblasts contributing greatly to peritendon thickening. Endotendon collagen disorganization was evident in week 12 HRHF tendons. LRNF tendons did not differ from controls, even at 12 weeks. Thus, we observed exposure-dependent changes in flexor digitorum tendons within the carpal tunnel, including increased inflammation, nociceptor-related neuropeptide immunoexpression, and fibrotic histopathology, changes associated with grip strength decline. Keywords: cytokines; inflammation; flexor digitorum tendon; repetitive task; PLF; CTGF; WMSD Tendinopathies of the hand and wrist tendons are associated with forceful repetition in the workplace. 1-3The incidence of flexor tenosynovitis is significantly higher in strenuous meat processing jobs: 25.3% for female packers, 16.8% for female sausage makers, and 12.5% for male meat cutters. The incidence in nonstrenuous jobs was less than 1% during a 31 month study period.4,5 Manufacturing workers performing highly repetitive and forceful jobs are 29 times more likely to develop wrist and hand tendonitis than workers performing low repetition and low force jobs. 5,6The etiology and pathophysiology of overuse-induced tendinopathies are still under investigation. Although the presence of an inflammatory component has not been identified by all investigators, 7-9 increased inflammatory molecules, for example, PGE 2 , have been found in tenosynovium of patients diagnosed with carpal tunnel syndrome (CTS), especially during the intermediate phase.10,11 However, PGE 2 was not found in tendon biopsies collected during the chronic painful tendinosis stage, although increased glutamate neurotransmitter and its receptor were evident. 8,9 The neurochemical Substance P is associated with chronic pain mediation 12 and has also been identif...

We examined the relationship between grip strength declines and muscle-tendon responses induced by long-term performance of a high-repetition, low-force (HRLF) reaching task in rats. We hypothesized that grip strength declines would correlate with inflammation, fibrosis and degradation in flexor digitorum muscles and tendons. Grip strength declined after training, and further in weeks 18 and 24, in reach limbs of HRLF rats. Flexor digitorum tissues of reach limbs showed low-grade increases in inflammatory cytokines: IL-1β after training and in week 18, IL-1α in week 18, TNF-α and IL-6 after training and in week 24, and IL-10 in week 24, with greater increases in tendons than muscles. Similar cytokine increases were detected in serum with HRLF: IL-1α and IL-10 in week 18, and TNF-α and IL-6 in week 24. Grip strength correlated inversely with IL-6 in muscles, tendons and serum, and TNF-α in muscles and serum. Four fibrogenic proteins, TGFB1, CTGF, PDGFab and PDGFbb, and hydroxyproline, a marker of collagen synthesis, increased in serum in HRLF weeks 18 or 24, concomitant with epitendon thickening, increased muscle and tendon TGFB1 and CTGF. A collagenolytic gelatinase, MMP2, increased by week 18 in serum, tendons and muscles of HRLF rats. Grip strength correlated inversely with TGFB1 in muscles, tendons and serum; with CTGF-immunoreactive fibroblasts in tendons; and with MMP2 in tendons and serum. Thus, motor declines correlated with low-grade systemic and musculotendinous inflammation throughout task performance, and increased fibrogenic and degradative proteins with prolonged task performance. Serum TNF-α, IL-6, TGFB1, CTGF and MMP2 may serve as serum biomarkers of work-related musculoskeletal disorders, although further studies in humans are needed.

Background:The structure and function of GPR35 are not understood. Results: Using a GPR35 activated state molecular model, we identified crucial amino acid residues required for ligand activation using ␤-arrestin trafficking, ERK1/2 activation, and calcium imaging. Conclusion: Arginines in TMH3-4-5-6 affected agonist signaling. Significance: Identification of residues for GPR35 agonist signaling is critical for the design of ligands with improved potency.

Nonagenarian patients receiving treatment had satisfactory tolerability and achieved expected survival rates post-RT.

We have shown that continued performance of repetitive tasks induces grip strength declines despite resolution of systemic inflammation. We hypothesize this is due to underlying tissue degeneration. Here, we assessed long term performance (18 weeks) of a high-repetition, low-force (HRLF) task in a rat model of reaching and grasping. We observed reduced grip strength immediately after training, and persistent grip strength declines in reach limbs of HRLF rats. Several inflammatory cytokines increased in serum of 6- and 12-week HRLF rats, e.g. tumor necrosis factor alpha (TNF-alpha). TNF- alpha was also increased in reach limb muscles and tendons at similar time points. A serum analyte of collagen degradation (matrix metalloproteinase-2, MMP2) was increased in serum of 18-week HRLF rats. MMP2 and several other MMPs, as well as two fibrogenic proteins (CTGF and TGFB1), were increased in 18-week HRLF tendons, which also showed histological signs of pathology. Thus, motor declines were associated earlier with tissue inflammation but later with tendon degenerative changes. Assaying for TNF- alpha and MMP2 provided important insights into the stages of inflammation and degradation in this model.