Update: cohort mortality study of workers highly exposed to polychlorinated biphenyls (PCBs) during the manufacture of electrical capacitors, 1940-1998

BACKGROUND: The National Institute for Occupational Safety and Health previously reported mortality for a cohort of workers considered highly exposed to polychlorinated biphenyls (PCBs) between 1939 and 1977 at two electrical capacitor manufacturing plants. The current study updated vital status, examined liver and rectal cancer mortality previously reported in excess in this cohort and evaluated mortality from non-Hodgkin's lymphoma (NHL) and cancers of the stomach, intestine, breast, prostate, skin (melanoma) and brain reported to be in excess in other cohort and case-control studies of PCB-exposed persons. METHODS: Mortality was updated through 1998 for 2572 workers. Age-, gender-, race- and calendar year-adjusted standardized mortality ratios (SMRs) and 95% confidence intervals (CI) were calculated using U.S., state and county referent rates. SMRs using U.S. referent rates are reported. Duration of employment was used as a surrogate for exposure. RESULTS: Consistent with the previous follow-up, mortality from biliary passage, liver and gall bladder cancer was significantly elevated (11 deaths, SMR 2.11, CI 1.05 – 3.77), but mortality from rectal cancer was not (6 deaths, SMR 1.47, CI 0.54 – 3.21). Among women, mortality from intestinal cancer (24 deaths, SMR 1.89, CI 1.21 – 2.82) and from "other diseases of the nervous system and sense organs", which include Parkinson's disease and amyotrophic lateral sclerosis, (15 deaths, SMR 2.07, CI 1.16 – 3.42) were elevated. There were four ALS deaths, all women (SMR 4.35, CI 1.19–11.14). Mortality was elevated for myeloma (7 deaths, SMR 2.11, CI 0.84 – 4.34), particularly among workers employed 10 years or more (5 deaths, SMR 2.80, CI 0.91 – 6.54). No linear associations between mortality and duration of employment were observed for the cancers of interest. CONCLUSION: This update found that the earlier reported excess in this cohort for biliary, liver and gall bladder cancer persisted with longer follow-up. Excess mortality for intestinal cancer among women was elevated across categories of duration of employment; myeloma mortality was highest among those working 10 years or more. The small numbers of deaths from liver and intestinal cancers, myeloma and nervous system diseases coupled with the lack of an exposure-response relationship with duration of employment preclude drawing definitive conclusions regarding PCB exposure and these causes of death

Design and Analysis of Rhesus Cytomegalovirus IL-10 Mutants as a Model for Novel Vaccines against Human Cytomegalovirus

Human cytomegalovirus (HCMV) expresses a viral ortholog (CMVIL-10) of human cellular interleukin-10 (cIL-10). Despite only ∼26% amino acid sequence identity, CMVIL-10 exhibits comparable immunosuppressive activity with cIL-10, attenuates HCMV antiviral immune responses, and contributes to lifelong persistence within infected hosts. The low sequence identity between CMVIL-10 and cIL-10 suggests vaccination with CMVIL-10 may generate antibodies that specifically neutralize CMVIL-10 biological activity, but not the cellular cytokine, cIL-10. However, immunization with functional CMVIL-10 might be detrimental to the host because of its immunosuppressive properties.Structural biology was used to engineer biologically inactive mutants of CMVIL-10 that would, upon vaccination, elicit a potent immune response to the wild-type viral cytokine. To test the designed proteins, the mutations were incorporated into the rhesus cytomegalovirus (RhCMV) ortholog of CMVIL-10 (RhCMVIL-10) and used to vaccinate RhCMV-infected rhesus macaques. Immunization with the inactive RhCMVIL-10 mutants stimulated antibodies against wild-type RhCMVIL-10 that neutralized its biological activity, but did not cross-react with rhesus cellular IL-10.This study demonstrates an immunization strategy to neutralize RhCMVIL-10 biological activity using non-functional RhCMVIL-10 antigens. The results provide the methodology for targeting CMVIL-10 in vaccine, and therapeutic strategies, to nullify HCMV's ability to (1) skew innate and adaptive immunity, (2) disseminate from the site of primary mucosal infection, and (3) establish a lifelong persistent infection

Making direct democracy work: A rational-actor perspective on the graphe paranomon in ancient Athens

The specific way the Athenians set up their democracy presents both theoretical and empirical challenges. Decisions were taken by majority vote in the Assembly. To keep politicians in line, the Athenians first used ostracism, which however was replaced by the graphe paranomon around 415 BCE. The latter provided that anybody who had made a proposal in the Assembly could be accused of having made an unconstitutional suggestion, bringing a potentially severe penalty if found guilty. We know of 35 such cases between 403 and 322. During the fourth century the notion of illegality was extended to a mere question of political undesirability. Henceforth any decision by the Assembly could be overturned by the courts, but if the accuser failed to get at least 20% of the jury votes, he was punished instead. While these rules can be seen as a safeguard against bad decisions, they also provided the Athenian politicians with important information about the relative strength of their political support. This effect has not been analysed before, and it may help explain the relative stability of political life in classical Athens. Furthermore this analysis also contributes to our understanding of a curious but often overlooked fact, namely that the decrees of the Athenian Assembly to a great extent concerned honorary rewards, and the use of the graphe paranomon in turn was largely focussed on the honorary decrees