Release of soluble metal ions from copper based dental alloys mesured by ICP-MS

Describes the release of soluble metal ions from copper based dental alloys mesured by ICP-MS. Presented at the annual congress of the british toxicology society

A truncated lipoglycan from mycobacteria with altered immunological properties

Maintenance of cell-wall integrity in Mycobacterium tuberculosis is essential and is the target of several antitubercular drugs. For example, ethambutol targets arabinogalactan and lipoarabinomannan (LAM) biosynthesis through the inhibition of several arabinofuranosyltransferases. Apart from their role in cell-wall integrity, mycobacterial LAMs also exhibit important immunomodulatory activities. Here we report the isolation and detailed structural characterization of a unique LAM molecule derived from Mycobacterium smegmatis deficient in the arabinofuranosyltransferase AftC (AftC-LAM). This mutant LAM expresses a severely truncated arabinan domain completely devoid of 3,5-Araf–branching residues, revealing an intrinsic involvement of AftC in the biosynthesis of LAM. Furthermore, we found that ethambutol efficiently inhibits biosynthesis of the AftC-LAM arabinan core, unambiguously demonstrating the involvement of the arabinofuranosyltransferase EmbC in early stages of LAM-arabinan biosynthesis. Finally, we demonstrate that AftC-LAM exhibits an enhanced proinflammatory activity, which is due to its ability to activate Toll-like receptor 2 (TLR2). Overall, our efforts further describe the mechanism of action of an important antitubercular drug, ethambutol, and demonstrate a role for specific arabinofuranosyltransferases in LAM biosynthesis. In addition, the availability of sufficient amounts of chemically defined wild-type and isogenic truncated LAMs paves the way for further investigations of the structure–function relationship of TLR2 activation by mycobacterial lipoglycans

Onset of Mild Cognitive Impairment in Parkinson Disease

Objective: Characterize the onset and timing of cognitive decline in Parkinson disease (PD) from the first recognizable stage of cognitively symptomatic PD-mild cognitive impairment (PD-MCI) to PD dementia (PDD). Thirty-nine participants progressed from PD to PDD and 25 remained cognitively normal. Methods: Bayesian-estimated disease-state models described the onset of an individual’s cognitive decline across 12 subtests with a change point. Results: Subtests measuring working memory, visuospatial processing ability, and crystalized memory changed significantly 3 to 5 years before their first nonzero Clinical Dementia Rating and progressively worsened from PD to PD-MCI to PDD. Crystalized memory deficits were the hallmark feature of imminent conversion of cognitive status. Episodic memory tasks were not sensitive to onset of PD-MCI. For cognitively intact PD, all 12 subtests showed modest linear decline without evidence of a change point. Conclusions: Longitudinal disease-state models support a prodromal dementia stage (PD-MCI) marked by early declines in working memory and visuospatial processing beginning 5 years before clinical diagnosis of PDD. Cognitive declines in PD affect motor ability (bradykinesia), working memory, and processing speed (bradyphrenia) resulting in PD-MCI where visuospatial imagery and memory retrieval deficits manifest before eventual development of overt dementia. Tests of episodic memory may not be sufficient to detect and quantify cognitive decline in PD

Glucose Metabolism and Liver Fat in Early Life:Population studies from pregnancy until childhood: The Generation R Study

The first objective of this thesis was to examine the hypothesis that maternal early-pregnancy glucose concentrations are associated with adverse fetal, pregnancy, birth and child cardio-metabolic outcomes. Also, as second objective, we studied potential determinants of a specific outcome, childhood liver fat, as well as the cardio-metabolic consequences of childhood liver fa