Long-term exposure to anticholinergic and sedative medications and cognitive and physical function in later life

Background: Anticholinergic and sedative medications are frequently prescribed to older individuals. These medications are associated with short-term cognitive and physical impairment, but less is known about long-term associations. We therefore examined over twenty years whether cumulative exposure to these medications was related to poorer cognitive and physical functioning. Methods: Older adult participants of the Longitudinal Aging Study Amsterdam (LASA) were followed from 1992-2012. On 7 measurement occasions, cumulative exposure to anticholinergic and sedative medications was quantified with the Drug Burden Index (DBI), a linear additive pharmacological dose-response model. Cognitive functioning was assessed with the Mini Mental State Examination (MMSE), Alphabet Coding Task (ACT, 3 trials), Auditory Verbal Learning Test (AVLT, learning and retention condition), and Raven Colored Progressive Matrices (RCPM, 2 trials). Physical functioning was assessed with the Walking Test (WT), Cardigan Test (CT), Chair Stands Test (CST), Balance Test (BT), and self-reported Functional Independence (FI). Data were analyzed with linear mixed models adjusted for age, education, sex, living with a partner, BMI, depressive symptoms, co-morbidities (cardiovascular disease, diabetes, cancer, COPD, osteoarthritis, CNS diseases), and prescribed medications. Results: Longitudinal associations were found of the DBI with poorer cognitive functioning (less items correct on the 3 ACT trials, AVLT learning condition, and the 2 RCPM trials) and with poorer physical functioning (longer completion time on the CT, CST, and lower self-reported FI). Conclusions: This longitudinal analysis of data collected over 20 years, showed that higher long-term cumulative exposure to anticholinergic and sedative medications was associated with poorer cognitive and physical functioning

Phevalin (aureusimine B)Production by <em>Staphylococcus aureus</em> Biofilm and Impacts on Human Keratinocyte Gene Expression

<div><p><em>Staphylococcus aureus</em> biofilms are associated with chronic skin infections and are orders of magnitude more resistant to antimicrobials and host responses. <em>S. aureus</em> contains conserved nonribosomal peptide synthetases that produce the cyclic dipeptides tyrvalin and phevalin (aureusimine A and B, respectively). The biological function of these compounds has been speculated to be involved in virulence factor gene expression in <em>S. aureus</em>, protease inhibition in eukaryotic cells, and interspecies bacterial communication. However, the exact biological role of these compounds is unknown. Here, we report that <em>S. aureus</em> biofilms produce greater amounts of phevalin than their planktonic counterparts. Phevalin had no obvious impact on the extracellular metabolome of <em>S. aureus</em> as measured by high-performance liquid chromatography-mass spectrometry and nuclear magnetic resonance. When administered to human keratinocytes, phevalin had a modest effect on gene expression. However, conditioned medium from <em>S. aureus</em> spiked with phevalin amplified differences in keratinocyte gene expression compared to conditioned medium alone. Phevalin may be exploited as potential biomarker and/or therapeutic target for chronic, <em>S. aureus</em> biofilm-based infections.</p> </div

<i>S. aureus</i> biofilms produce more phevalin than their planktonic counterparts.

<p>(A) HPLC-MS analysis of organic extracts from <i>S. aureus</i> biofilm, planktonic, and growth medium control revealed that biofilms produce more phevalin (aureusimine B) than planktonic cultures (arrow). A compound that is likely tyrvalin (aureusimine A) was also present at higher levels in the biofilm (*). (B) Phevalin production was detected directly in samples without prior organic extraction. Samples were normalized to cell density (optical density, 600 nm, OD₆₀₀) in biofilm (OD₆₀₀ 0.9), resuspended biofilm (OD₆₀₀ 1.4), and planktonic cultures (OD₆₀₀ 0.66). Data represent means ± SEM, n = 3, ***p<0.001.</p

Conditioned medium from <i>S. aureus</i> cultures with or without additional phevalin induces differential gene expression in HKs.

<p>Significant (p<0.05) transcripts regulated ±2 fold in any one condition relative to controls. Transcripts shared between HKs treated with BCM, +PCM, and –PCM are shown at ±2 and ±5 fold change cutoffs (A and B, respectively). HKs treated with BCM shared more transcripts with +PCM treated HKs than –PCM treated HKs (arrows). Transcripts shared between –PCM and BCM had modest fold changes as no transcripts were shared above the ±5 FC cutoff. (C) The top 20 upregulated and downregulated genes (p<0.05) in +PCM treated HKs relative to –PCM treated HKs are listed. For a complete list of significantly regulated genes, see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040973#pone.0040973.s003" target="_blank">Table S1</a>. (D) Selected genes were confirmed by RT-qPCR. The fold change relative to a GAPDH normalizer is indicated (p<0.05 for all comparing DMSO to phevalin). (E) Functional annotation clustering of microarray data revealed significantly (Benjamini p<0.01) enriched biological processes in +PCM treated HKs.</p

Phevalin production in various strains of bacteria as detected by SRM HPLC-MS.

<p>Phevalin production in various strains of bacteria as detected by SRM HPLC-MS.</p