Lifestyle predicts falls independent of physical risk factors

Many falls occur among older adults with no traditional risk factors. We examined potential independent effects of lifestyle on fall risk. Not smoking and going outdoors frequently or infrequently were independently associated with more falls, indicating lifestyle-related behavioral and environmental risk factors are important causes of falls in older women. Physical and lifestyle risk factors for falls and population attributable risks (PAR) were examined. We conducted a 4-year prospective study of 8,378 community-dwelling women (mean age = 71 years, SD = 3) enrolled in the Study of Osteoporotic Fractures. Data on number of falls were self-reported every 4 months. Fall rates were calculated (# falls/woman-years). Poisson regression was used to estimate relative risks (RR). Physical risk factors (p ≤ 0.05 for all) included tall height (RR = 0.89 per 5 in.), dizziness (RR = 1.16), fear of falling (RR = 1.20), self-reported health decline (RR = 1.19), difficulty with Instrumental Activities of Daily Living (IADLs) (RR = 1.12, per item), fast usual-paced walking speed (RR = 1.18, per 2 SD), and use of antidepressants (RR = 1.20), benzodiazepines (RR = 1.11), or anticonvulsants (RR = 1.62). Protective physical factors (p ≤ 0.05 for all) included good visual acuity (RR = 0.87, per 2 SD) and good balance (RR = 0.85 vs. poor). Lifestyle predicted fewer falls including current smoking (RR = 0.76), going outdoors at least twice weekly but not more than once a day (RR = 0.89 and vs. twice daily). High physical activity was associated with more falls but only among IADL impaired women. Five potentially modifiable physical risk factors had PAR ≥ 5%. Fall interventions addressing modifiable physical risk factors with PAR ≥ 5% while considering environmental/behavioral risk factors are indicated

mTOR: from growth signal integration to cancer, diabetes and ageing

In all eukaryotes, the target of rapamycin (TOR) signalling pathway couples energy and nutrient abundance to the execution of cell growth and division, owing to the ability of TOR protein kinase to simultaneously sense energy, nutrients and stress and, in metazoans, growth factors. Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt. In the past few years, a significant advance in our understanding of the regulation and functions of mTOR has revealed the crucial involvement of this signalling pathway in the onset and progression of diabetes, cancer and ageing.National Institutes of Health (U.S.)Howard Hughes Medical InstituteWhitehead Institute for Biomedical ResearchJane Coffin Childs Memorial Fund for Medical Research (Postdoctoral Fellowship)Human Frontier Science Program (Strasbourg, France

Vulnerability of Architectural Heritage in Seismic Areas: Constructive Aspects and Effect of Interventions

In this chapter, the effects of past interventions applied to historical city centers struck by a series of earthquakes over time are analyzed in terms of local and overall damage. Three villages in central Italy, Castelluccio di Norcia, Campi Alto di Norcia and Castelsantangelo sul Nera, containing overall about 150 buildings, are examined here. Classification of damage was based on the European Macroseismic Scale. The study provided vulnerability maps detailing the influence of interventions on buildings in historical city centers, which may contribute to better evaluation of damage scenario and maintenance plans

Inhibition of Dopamine Transporter sctivity by G protein beta gamma subunits

Uptake through the Dopamine Transporter (DAT) is the primary mechanism of terminating dopamine signaling within the brain, thus playing an essential role in neuronal homeostasis. Deregulation of DAT function has been linked to several neurological and psychiatric disorders including ADHD, schizophrenia, Parkinson’s disease, and drug addiction. Over the last 15 years, several studies have revealed a plethora of mechanisms influencing the activity and cellular distribution of DAT; suggesting that fine-tuning of dopamine homeostasis occurs via an elaborate interplay of multiple pathways. Here, we show for the first time that the βγ subunits of G proteins regulate DAT activity. In heterologous cells and brain tissue, a physical association between Gβγ subunits and DAT was demonstrated by co-immunoprecipitation. Furthermore, in vitro pull-down assays using purified proteins established that this association occurs via a direct interaction between the intracellular carboxy-terminus of DAT and Gβγ. Functional assays performed in the presence of the non-hydrolyzable GTP analog GTP-γ-S, Gβγ subunit overexpression, or the Gβγ activator mSIRK all resulted in rapid inhibition of DAT activity in heterologous systems. Gβγ activation by mSIRK also inhibited dopamine uptake in brain synaptosomes and dopamine clearance from mouse striatum as measured by high-speed chronoamperometry in vivo. Gβγ subunits are intracellular signaling molecules that regulate a multitude of physiological processes through interactions with enzymes and ion channels. Our findings add neurotransmitter transporters to the growing list of molecules regulated by G-proteins and suggest a novel role for Gβγ signaling in the control of dopamine homeostasis.Jennie Garcia-Olivares, Delany Torres-Salazar, William A. Owens, Tracy Baust, David P. Siderovski, Susan G. Amara, Jun Zhu, Lynette C. Daws, Gonzalo E. Torre

Dopamine D4 receptor, but not the ADHD-associated D4.7 variant, forms functional heteromers with the dopamine D2S receptor in the brain

Polymorphic variants of the dopamine D4 receptor have been consistently associated with attention-deficit hyperactivity disorder (ADHD). However, the functional significance of the risk polymorphism (variable number of tandem repeats in exon 3) is still unclear. Here, we show that whereas the most frequent 4-repeat (D4.4) and the 2-repeat (D4.2) variants form functional heteromers with the short isoform of the dopamine D2 receptor (D2S), the 7-repeat risk allele (D4.7) does not. D2 receptor activation in the D2S-D4 receptor heteromer potentiates D4 receptor-mediated MAPK signaling in transfected cells and in the striatum, which did not occur in cells expressing D4.7 or in the striatum of knockin mutant mice carrying the 7 repeats of the human D4.7 in the third intracellular loop of the D4 receptor. In the striatum, D4 receptors are localized in corticostriatal glutamatergic terminals, where they selectively modulate glutamatergic neurotransmission by interacting with D2S receptors. This interaction shows the same qualitative characteristics than the D2S-D4 receptor heteromer-mediated mitogen-activated protein kinase (MAPK) signaling and D2S receptor activation potentiates D4 receptor-mediated inhibition of striatal glutamate release. It is therefore postulated that dysfunctional D2S-D4.7 heteromers may impair presynaptic dopaminergic control of corticostriatal glutamatergic neurotransmission and explain functional deficits associated with ADHD