The long-term hospitalization experience following military service in the 1991 Gulf War among veterans remaining on active duty, 1994–2004

<p>Abstract</p> <p>Background</p> <p>Despite more than a decade of extensive, international efforts to characterize and understand the increased symptom and illness-reporting among veterans of the 1991 Gulf War, concern over possible long-term health effects related to this deployment continue. The purpose of this study was to describe the long-term hospitalization experience of the subset of U.S. Gulf War veterans still on active duty between 1994 and 2004.</p> <p>Methods</p> <p>Gulf War veterans on active duty rosters as of October 1, 1994, were identified (n = 211 642) and compared with veterans who had separated from military service and then assessed for attrition at three-year intervals during a 10-year follow-up period, examining demographic and military service characteristics, Gulf War exposure variables, and hospitalization data. Cox proportional hazard modeling was used to evaluate independent predictors of all-cause hospitalization among those still on active duty and to estimate cumulative probability of hospitalization, 1994–2004, by service branch.</p> <p>Results</p> <p>Members of our 1994 active duty cohort were more likely to be officers, somewhat older, and married compared with those who had separated from the military after serving in the 1991 Gulf War. Selected war-related exposures or experiences did not appear to influence separation with the exception of in-theater presence during the brief ground combat phase. Overall the top three diagnostic categories for hospitalizations were musculo-skeletal, injury and poisoning, and digestive disorders. Diseases of the circulatory system and symptoms, signs, and ill-defined conditions increased proportionately over time. In-theater hospitalization was the only significant independent predictor of long-term hospitalization risk among selected war-related exposures or experiences examined. The cumulative probability of hospitalization was highest for Army and lowest for Marines.</p> <p>Conclusion</p> <p>Our results were generally consistent with a previous hospitalization study of US Gulf War veterans for the period August 1991 to July 1999. Although lack of a comparison group for our study limits interpretation of overall findings, intra-cohort analyses showed no significant associations between long-term hospitalization and war-related exposures or experiences, with the exception of in-theater hospitalization, within our active duty subset of 1991 Gulf War veterans.</p

RBR ligase–mediated ubiquitin transfer: a tale with many twists and turns

RBR ligases are an enigmatic class of E3 ubiquitin ligases that combine properties of RING and HECT-type E3s and undergo multilevel regulation through autoinhibition, post-translational modifications, multimerization and interaction with binding partners. Here, we summarize recent progress in RBR structures and function, which has uncovered commonalities in the mechanisms by which different family members transfer ubiquitin through a multistep process. However, these studies have also highlighted clear differences in the activity of different family members, suggesting that each RBR ligase has evolved specific properties to fit the biological process it regulates

Parkin–phosphoubiquitin complex reveals cryptic ubiquitin-binding site required for RBR ligase activity

RING-between-RING (RBR) E3 ligases are a class of ubiquitin ligases distinct from RING or HECT E3 ligases. An important RBR ligase is Parkin, mutations in which lead to early-onset hereditary Parkinsonism. Parkin and other RBR ligases share a catalytic RBR module but are usually autoinhibited and activated via distinct mechanisms. Recent insights into Parkin regulation predict large, unknown conformational changes during Parkin activation. However, current data on active RBR ligases reflect the absence of regulatory domains. Therefore, it remains unclear how individual RBR ligases are activated, and whether they share a common mechanism. We now report the crystal structure of a human Parkin–phosphoubiquitin complex, which shows that phosphoubiquitin binding induces movement in the 'in-between RING' (IBR) domain to reveal a cryptic ubiquitin-binding site. Mutation of this site negatively affects Parkin's activity. Furthermore, ubiquitin binding promotes cooperation between Parkin molecules, which suggests a role for interdomain association in the RBR ligase mechanism