Extracellular heat shock protein 70 inhibits tumour necrosis factor-alpha induced proinflammatory mediator production in fibroblast-like synoviocytes.

INTRODUCTION: It was recently suggested that heat shock protein (HSP)70, an intracellular protein, is a potential mediator of inflammatory disease when it is released into the extracellular compartment. Although elevated HSP70 levels have been identified in rheumatoid arthritis (RA) synovial tissues and RA synovial fluid compared with patients with osteoarthritis and healthy individuals, it remains unclear what role extracellular HSP70 plays in the pathogenesis of RA. This study was conducted to investigate the effects of extracellular HSP70 on the production of RA-associated cytokines in fibroblast-like synoviocytes from patients with RA and to elucidate the mechanisms involved. METHODS: IL-6, IL-8 and monocyte chemoattractant protein (MCP)-1 levels in culture supernatants were measured using enzyme-linked immunosorbent assays. Activation of mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated protein kinases (ERKs), c-Jun amino-terminal kinase (JNK) and p38 MAPK, was detected using Western blotting. Nuclear translocation of nuclear factor-kappaB (NF-kappaB) and degradation of the inhibitory protein IkappaBalpha were examined using immunohistochemistry and Western blotting. RESULTS: Human HSP70 downregulated IL-6, IL-8 and MCP-1 production in RA fibroblast-like synoviocytes induced by tumour necrosis factor (TNF)-alpha in a concentration dependent manner. HSP70 inhibited the activation of ERK, JNK and p38 MAPK in fibroblast-like synoviocytes stimulated by TNF-alpha. Furthermore, HSP70 also significantly inhibited nuclear translocation of nuclear factor-kappaB and degradation of IkappaBalpha induced by TNF-alpha. CONCLUSION: Extracellular HSP70 has an anti-inflammatory effect on RA by downregulating production of IL-6, IL-8 and MCP-1 in fibroblast-like synoviocytes, which is mediated through inhibited activation of the MAPKs and NF-kappaB signal pathways.

Injury and fitness outcomes during implementation of physical readiness training.

This study examined injury and physical fitness outcomes in Basic Combat Training (BCT) during implementation of Physical Readiness Training (PRT). PRT is the U.S. Army's emerging physical fitness training program. An experimental group (EG, n = 1284), which implemented the PRT program, was compared to a control group (CG, n = 1296), which used a traditional BCT physical training program during the 9-week BCT cycle. Injury cases were obtained from recruit medical records and physical fitness was measured using the U.S. Army Physical Fitness Test (APFT, consisting of push-ups, sit-ups and a two-mile run). Injury rates were examined using Cox regression after controlled for initial group differences in demographics, fitness and other variables. Compared to the EG, the adjusted relative risk of a time-loss overuse injury in the CG was 1.5 (95 % confidence interval [CI] = 1.0 - 2.1, p < 0.01) for men and 1.4 (95 %CI = 1.1 - 1.8, p < 0.01) for women. There were no differences between groups for traumatic injuries. On the first administration of the final APFT, the EG had a greater proportion of recruits passing the test than the CG (men: 85 % vs. 81 %, p = 0.04; women: 80 % vs. 70 %, p < 0.01). After all APFT retakes, the EG had significantly fewer APFT failures than the CG among the women (1.6 % vs. 4.6 %, p < 0.01) but not the men (1.6 % vs. 2.8 %, p = 0.18); the gender-combined EG had a higher pass rate (1.6 % vs. 3.7 %, p < 0.01). Overall, the PRT program reduced overuse injuries and allowed a higher success rate on the APFT.

Ulnar neuropathy associated with subdermal contraceptive implant.

Side effects are a common occurrence in the use of subdermal contraceptive implants (Norplant); approximately 70% to 80% of women using the device report abnormal uterine bleeding, headaches, acne, mastalgia, nervousness, appetite changes, and weight gain. Local implant site reactions range from 0.4% to 4.7%, with pain being the most common. Other insertion site complications include infection and implant expulsion. Only three cases have been described in the literature concerning implant site-related neuropathy, involving the sensory branch of the musculocutaneous nerve (lateral cutaneous nerve) in two cases and the antebrachial cutaneous nerve in the third case. We believe our report is the first case of an axonal loosing motor and sensory ulnar neuropathy associated with the removal of a subdermal contraceptive implant (Norplant). We review insertion site complications and their most likely causes. Also, we discuss alternative removal techniques for difficult-to-remove implants.

Effects of pentobarbital and d-amphetamine on the repeated acquisition of response sequences by pigeons.

Pigeons were trained to acquire a new 4-response sequence in each session by pecking three keys in a predetermined order. The key color varied for each step under the chained schedule, but there was only one key color under the tandem schedule. Under the reset contingency, incorrect responses produced a reset of the 4-response sequence to its beginning and a short timeout. In the non-resent contingency, only the timeout was produced by incorrect responses. Under both contingencies of both schedules, low doses (3-10 mg/kg) of pentobarbital increased the response rate and the total number of errors, although the rate increases usually occurred at lower doses than did the increases in errors. A dose of 17.5 mg/kg pentobarbital eliminated almost all responding. Injection of low doseas (0.1 -0.3 mg/kg) of d-amphetamine decreased the total number of errors under both contingencies of both the chained and the tandem schedules. Higher doses of d-amphetamine sometimes increased the total number of errors and decreased the response rate.