Aging and the Environment: A Research Framework

The rapid growth in the number of older Americans has many implications for public health, including the need to better understand the risks posed to older adults by environmental exposures. Biologic capacity declines with normal aging; this may be exacerbated in individuals with pre-existing health conditions. This decline can result in compromised pharmacokinetic and pharmacodynamic responses to environmental exposures encountered in daily activities. In recognition of this issue, the U.S. Environmental Protection Agency (EPA) is developing a research agenda on the environment and older adults. The U.S. EPA proposes to apply an environmental public health paradigm to better understand the relationships between external pollution sources → human exposures → internal dose → early biologic effect → adverse health effects for older adults. The initial challenge will be using information about aging-related changes in exposure, pharmacokinetic, and pharmacodynamic factors to identify susceptible subgroups within the diverse population of older adults. These changes may interact with specific diseases of aging or medications used to treat these conditions. Constructs such as “frailty” may help to capture some of the diversity in the older adult population. Data are needed regarding a) behavior/activity patterns and exposure to the pollutants in the microenvironments of older adults; b) changes in absorption, distribution, metabolism, and excretion with aging; c) alterations in reserve capacity that alter the body’s ability to compensate for the effects of environmental exposures; and d) strategies for effective communication of risk and risk reduction methods to older individuals and communities. This article summarizes the U.S. EPA’s development of a framework to address and prioritize the exposure, health effects, and risk communications concerns for the U.S. EPA’s evolving research program on older adults as a susceptible subpopulation

Mammalian Frataxin: An Essential Function for Cellular Viability through an Interaction with a Preformed ISCU/NFS1/ISD11 Iron-Sulfur Assembly Complex

Frataxin, the mitochondrial protein deficient in Friedreich ataxia, a rare autosomal recessive neurodegenerative disorder, is thought to be involved in multiple iron-dependent mitochondrial pathways. In particular, frataxin plays an important role in the formation of iron-sulfur (Fe-S) clusters biogenesis.. Fe-S cluster biosynthesis

Health-related preferences of older patients with multimorbidity: An evidence map

Objectives To systematically identify knowledge clusters and research gaps in the health-related preferences of older patients with multimorbidity by mapping current evidence.Design Evidence map (systematic review variant).Data sources MEDLINE, EMBASE, PsycINFO, PSYNDEX, CINAHL and Science Citation Index/Social Science Citation Index/-Expanded from inception to April 2018.Study selection Studies reporting primary research on health-related preferences of older patients (mean age ≥60 years) with multimorbidity (≥2 chronic/acute conditions).Data extraction Two independent reviewers assessed studies for eligibility, extracted data and clustered the studies using MAXQDA-18 content analysis software.Results The 152 included studies (62% from North America, 28% from Europe) comprised 57 093 patients overall (range 9–9105). All used an observational design except for one interventional study: 63 (41%) were qualitative (59 cross-sectional, 4 longitudinal), 85 (57%) quantitative (63 cross-sectional, 22 longitudinal) and 3 (2%) used mixed methods. The setting was specialised care in 85 (56%) and primary care in 54 (36%) studies. We identified seven clusters of studies on preferences: end-of-life care (n=51, 34%), self-management (n=34, 22%), treatment (n=32, 21%), involvement in shared decision making (n=25, 17%), health outcome prioritisation/goal setting (n=19, 13%), healthcare service (n=12, 8%) and screening/diagnostic testing (n=1, 1%). Terminology (eg, preferences, views and perspectives) and concepts (eg, trade-offs, decision regret, goal setting) used to describe health-related preferences varied substantially between studies.Conclusion Our study provides the first evidence map on the preferences of older patients with multimorbidity. Included studies were mostly conducted in developed countries and covered a broad range of issues. Evidence on patient preferences concerning decision-making on screening and diagnostic testing was scarce. Differences in employed terminology, decision-making components and concepts, as well as the sparsity of intervention studies, are challenges for future research into evidence-based decision support seeking to elicit the preferences of older patients with multimorbidity and help them construct preferences.Trial registration number Open Science Framework (OSF): DOI 10.17605/OSF.IO/MCRWQ

Effects of microperfusion in hepatic diffusion weighted imaging

Clinical hepatic diffusion weighted imaging (DWI) generally relies on mono-exponential diffusion. The aim was to demonstrate that mono-exponential diffusion in the liver is contaminated by microperfusion and that the bi-exponential model is required. Nineteen fasting healthy volunteers were examined with DWI (seven b-values) using fat suppression and respiratory triggering (1.5 T). Five different regions in the liver were analysed regarding the mono-exponentially fitted apparent diffusion coefficient (ADC), and the bi-exponential model: molecular diffusion (D (slow) ) microperfusion (D (fast) ) and the respective fractions (f (slow/fast)). Data were compared using ANOVA and Kruskal-Wallis tests. Simulations were performed by repeating our data analyses, using just the DWI series acquired with b-values approximating those of previous studies. Median mono-exponentially fitted ADCs varied significantly (P <0.001) between 1.107 and 1.423 x 10(-3) mm(2)/s for the five regions. Bi-exponential fitted D-slow varied between 0.923 and 1.062 x 10(-3) mm(2)/s without significant differences (P = 0.140). D (fast) varied significantly, between 17.8 and 46.8 x 10(-3) mm(2)/s (P <0.001). F-tests showed that the diffusion data fitted the bi-exponential model significantly better than the mono-exponential model (F > 21.4, P <0.010). These results were confirmed by the simulations. ADCs of normal liver tissue are significantly dependent on the measurement location because of substantial microperfusion contamination; therefore the bi-exponential model should be used. Diffusion weighted MR imaging helps clinicians to differentiate tumours by diffusion properties Fast moving water molecules experience microperfusion, slow molecules diffusion Hepatic diffusion should be measured by bi-exponential models to avoid microperfusion contamination Mono-exponential models are contaminated with microperfusion, resulting in apparent regional diffusion differences Bi-exponential models are necessary to measure diffusion and microperfusion in the liver

MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer

Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa