No abstract

Misfolded alpha-synuclein (AS) and other neurodegenerative disorder proteins display prion-like transmission of protein aggregation. Factors responsible for the initiation of AS aggregation are unknown. To evaluate the role of amyloid proteins made by the microbiota we exposed aged rats and transgenic C. elegans to E. coli producing the extracellular bacterial amyloid protein curli. Rats exposed to curli-producing bacteria displayed increased neuronal AS deposition in both gut and brain and enhanced microgliosis and astrogliosis compared to rats exposed to either mutant bacteria unable to synthesize curli, or to vehicle alone. Animals exposed to curli producing bacteria also had more expression of TLR2, IL-6 and TNF in the brain than the other two groups. There were no differences among the rat groups in survival, body weight, inflammation in the mouth, retina, kidneys or gut epithelia, and circulating cytokine levels. AS-expressing C. elegans fed on curli-producing bacteria also had enhanced AS aggregation. These results suggest that bacterial amyloid functions as a trigger to initiate AS aggregation through cross-seeding and also primes responses of the innate immune system.

The authors linked interview data drawn from Utah participants in the Diet, Activity, and Reproduction in Colon Cancer (DARCC) Study (1992-1995) to genealogic and cancer information contained in the Utah Population Database (UPDB). They evaluated the sensitivity of subjects' reports of familial cancers and measured the overall agreement between reported and database records with the kappa (kappa) statistic. They calculated odds ratios from logistic regression to compare the relative risk estimates that would result from use of either data set (or both data sets). Overall, 37.6% (331 of 881) of the Utah DARCC subjects were linked to the UPDB genealogy. High sensitivities were observed for subjects' reports of breast (83%), colorectal (73%), and prostate (70%) cancers, while ovarian (60%) and uterine (30%) cancers were not reported as well. Results for kappa were similar, with values of 0.63 for breast cancer and 0.56 for colorectal cancer. Although the observed kappa s of 0.36 and 0.25 for ovarian and uterine cancers, respectively, exceeded chance expectations, the agreement between subjects' reports and database records was unimpressive. No consistent difference was observed between cases and controls in the accuracy of self-reports. In general, higher sensitivities were observed among younger subjects than older subjects; females reported family histories of cancer only slightly better than males. A college education was not consistently associated with more accurate reporting of family history of cancer. These results indicate that subjects in a case-control study are able to report accurately family histories of several common kinds of cancer and that they can do so without observable recall bias. The accuracy of self-reports may not be adequate for reproductive tract cancers and cancers such as rectal cancer that are frequently confused with cancers of similar organs.

We evaluated the influence of family history on longevity by examining longevity in a cohort of 78,994 individuals drawn from the Utah Population Database (UPDB) who were born between 1870 and 1907, and lived to at least age 65. We examined Mendelian genetic and social modes of transmission of excess longevity (the difference between observed and expected longevity) by varying weighted kinship contributions over different classes of relatives. The genetic component of the variation in excess longevity measured as heritability, h2, was approximately 0.15 (95% confidence interval [CI] 0.12-0.18). Among siblings of probands who reached the 97th percentile of excess longevity (+ 14.8 years, currently age 95 for men and 97 for women), the relative risk of recurrence (lambdas) was 2.30 (95% CI 2.08-2.56). In sibships whose relatives were in the top 15% of the distribution for familial excess longevity, the value of lambdas increased substantially, indicating that considering the longevity of distant relatives may be helpful in the selection of families in which to identify genes influencing aging and longevity.