Interest because tissues collected from humans with upper extremity work-related musculoskeletal disorders show the presence of fibrosis and its mediators, including IL-6 and TGFB1. IL-1b and TNF-a have also been deemed pro-fibrotic, due to their mitogenic and chemotactic effects on fibroblasts and induction of TGFB1. We postulate that IL-1b, TNF-a IL-6 increase at points of tissue injury or worsening tissue injury, and that their persistent increase is contributing to the later appearing fibrotic responses. As stated in the introduction, TGFB1 and CTGF are sensitive serum biomarkers of fibrogenic diseases. This is the first time, to our knowledge, that serum increases of either have been linked to work-related musculoskeletal disorders. Several studies have shown that TGFB1 and CTGF increase in tissues under conditions of overload or injury. Increases of TGFB1, CTGF and IL-6, have been linked to the pathogenesis of tissue fibrosis.These features may also hamper its interaction with coupling molecules such lipid binding proteins, CD14 and MD-2, as suggested elsewhere. In addition to LPS, there are other PAMP bearing molecules in the gram-negative OM. Based on the analysis of the activity of B. abortus BLPs purified from recombinant E. coli, it has been proposed that they are key elements triggering proinflammatory responses. In our work, the cytokine levels induced in vitro and in vivo by live and HK-Brucella as well as by OMF are far lower than those induced by Salmonella. We speculated that differing biobehavioral risk profiles were unlikely to account for the reduced incidence of cirrhosis in untreated patients since many of these would be predicted to increase, rather than reduce fibrosis progression. We used two alternative strategies to statistically adjust for these potential confounders in our Cox proportional hazards models. Using either adjustment method, treatment nonresponders were found to have a significantly greater hazard of developing cirrhosis than the never treated group a finding that was observed in the both the SFVA and UCSF cohorts. Some differences between treated and never treated patients were identified that could not be completely corrected in our statistical models. Treated patients were followed for approximately 1.5 years longer than never treated patients and had, on average, one additional diagnostic procedure. Both the duration of follow-up and the number of diagnostic procedures were entered into predictive models, but were not found to be confounders for either outcome. It is still possible that unmeasured confounding factors linked to treatment failure may have biased the results, but rigorous data collection, robust statistical methods, and the stability of a significant hazard ratio for cirrhosis among nonresponders in both cohorts make a compelling case for the validity of these findings. Furthermore the congruence of the findings from two diverse patient populations the SFVA cohort comprised of comparably aged veterans with similar risk behavior histories and the more demographically diverse UCSF cohort suggest that these results may be generalizable.In addition. With the current knowledge that GML are present in the MS brain, it is unknown whether IL1 contributing to MS/EAE pathology is just solely present in WML as has been focused upon thus far, or whether it is also present in GML.