Screening the ToxCast Phase 1, Phase 2, and e1k Chemical Libraries for Inhibitors of Iodothyronine Deiodinases.

Deiodinase enzymes play an essential role in converting thyroid hormones between active and inactive forms by deiodinating the pro-hormone thyroxine (T4) to the active hormone triiodothyronine (T3) and modifying T4 and T3 to inactive forms. Chemical inhibition of deiodinase activity has been identified as an important endpoint to include in screening chemicals for thyroid hormone disruption. To address the lack of data regarding chemicals that inhibit the deiodinase enzymes, we developed robust in vitro assays that utilized human deiodinase types 1, 2, and 3 and screened over 1800 unique chemicals from the U.S. EPA's ToxCast phase 1_v2, phase 2, and e1k libraries. Initial testing at a single concentration identified 411 putative deiodinase inhibitors that produced inhibition of 20% or greater in at least 1 of the 3 deiodinase assays, including chemicals that have not previously been shown to inhibit deiodinases. Of these, 228 chemicals produced enzyme inhibition of 50% or greater; these chemicals were further tested in concentration-response to determine relative potency. Comparisons across these deiodinase assays identified 81 chemicals that produced selective inhibition, with 50% inhibition or greater of only 1 of the deiodinases. This set of 3 deiodinase inhibition assays provides a significant contribution toward expanding the limited number of in vitro assays used to identify chemicals with the potential to interfere with thyroid hormone homeostasis. In addition, these results set the groundwork for development and evaluation of structure-activity relationships for deiodinase inhibition, and inform targeted selection of chemicals for further testing to identify adverse outcomes of deiodinase inhibition.

Predictors of progression to severe Alzheimer's disease in an incidence sample.

BACKGROUND: Little is known about factors influencing time to severe Alzheimer's disease (AD). METHODS: Incident cases of AD in the cache county memory study were identified. Severe AD was defined as mini-mental state examination score of ≤10 or Clinical Dementia Rating Scale score of 3; cases with either mini-mental state examination score of ≥16 or clinical dementia rating <2 were not categorized as severe AD. Kaplan-Meier, log-rank tests, and Cox analyses were used to identify demographic, clinical, and genetic correlates of time to progression to severe AD. RESULTS: Sixty-eight of 335 cases of incident AD developed severe dementia. In bivariate analyses, female gender, less than high school education, at least one clinically significant Neuropsychiatric Inventory domain at baseline, and the youngest and oldest ages exhibited shorter time to severe AD. In competing risk analysis, subjects with mild or at least one clinically significant neuropsychiatric inventory domain score, and subjects with worse health were more likely to progress to severe dementia or death. CONCLUSIONS: Demographic and clinical variables predict progression to severe AD. Further study should examine whether these relationships are causal or correlational.

Underreporting of blood and body fluid exposures among health care students and trainees in the acute care setting: a 2007 survey.

BACKGROUND: It has been estimated that more than 8 million health care workers (HCWs) in the United States may be exposed to blood and body fluids via sharp and mucocutaneous exposures. METHODS: An anonymous questionnaire was distributed among 505 HCWs. The target sample population included all the medical students; nursing professionals; dental professionals; and residents in internal medicine, emergency medicine, surgery, and obstetrics and gynecology at the University of Illinois Medical Center, Chicago, Illinois, a metropolitan tertiary care and referral center for Northern Illinois and Northwest Indiana. The sample was limited by the number of HCWs who were available to take the survey. The number and the characteristics of occupational exposures and reporting practices were recorded and compiled. Subsequently, a review of the English literature was performed using PubMed to analyze reasons for underreporting. Secondary and tertiary articles were located based on findings from the initial searches. RESULTS: One hundred three of 455 (22.6%) HCWs reported a sharps exposure during their career, including their student years; thirty-four (33.0%) of these were not reported. One hundred five of 455 (23.1%) HCWs reported a mucocutaneous exposure during their career; 87 (82.9%) of these were not reported. The most common year of exposure was the intern year. The most common reason for not reporting was the belief that the exposure was not significant, followed by the combination of believing the exposure was not significant and being too busy. CONCLUSION: Underreporting of blood and body fluid exposures is common because of a belief that most exposures are not significant. More education of HCWs is needed to change this perspective.