Citations

A recently identified variant within the fat mass and obesity-associated ( FTO ) gene is carried by 46% of Western Europeans and is associated with an ~1.2 kg higher weight, on average, in adults and an ~1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of ~8% in the frontal lobes and 12% in the occipital lobes—these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly.

Objective: This study aimed to determine the effects of active workstation designs on speed and error during typing, mouse pointing, and combined type and mouse-use tasks. Background: Office ergonomics has focused on musculoskeletal disorder prevention; however, increasing computer-based work also increases health risks associated with inactivity. Workstations allowing computer users to walk or cycle while performing computer tasks have been shown to demand sufficient energy expenditure to result in significant health benefits. However the performance effects of being active while using a computer have not been documented. Method: Thirty office workers (16 female, 15 touch typists) performed standardized computer tasks in six workstation conditions: sitting, standing, walking at 1.6 km/h and 3.2 km/h, and cycling at 5 and 30 watts. Performance, perceived performance, and heart rate were measured. Results: Computer task performance was lower when walking and slightly lower when cycling, compared with chair sitting. Standing performance was not different from sitting performance. Mouse performance was more affected than typing performance. Performance decrements were equal for females and males and for touch typists and nontouch typists. Conclusion: Performance decrements maybe related to both biomechanical and cognitive processes. Active workstations may be less suitable for mouse-intensive work and susceptible users. Application: Although active workstations may result in some decrement in performance, their ability to increase daily energy expenditure may make them a feasible solution for workplace inactivity.

We compared measures of ID coronary atherosclerosis between diabetic and non-diabetic patients enrolled in a prospective multinational IVUS registry. The region of interest was the most diseased 10 mm segment of a single coronary artery. Coronary plaque was quantified using greyscale IVUS and further classified by phenotype (ID-adaptive intimal thickening, ID-pathological intimal thickening, ID-TCFA, ID-fibroatheroma, or ID-fibrocalcific) using VH-IVUS. There was a non-significant trend for greater total plaque volume in diabetic (n=191) compared with non-diabetic (n=584) patients (94.8 vs. 88.1 mm 3 , p=0.36, adjusted for multiple comparisons). There was a greater proportion of ID-TCFA among diabetic patients (21.6 vs. 13.6%, p=0.01 after adjustment for multiple comparisons; p=0.08 following multivariable adjustment for age and clinical demographics), while differences in pathological intimal thickening, fibroatheroma and fibrocalcific plaque were not significant between groups. ID-TCFA was more common in the most diseased 10 mm segment of diabetic than in non-diabetic coronary arteries. Multivariable adjustment demonstrated age and possibly the presence of diabetes to be independent predictors of ID-TCFA.

A hallmark of the pathology of Alzheimer's disease is the accumulation of the microtubule-associated protein tau into fibrillar aggregates. Recent studies suggest that they accumulate because cytosolic chaperones fail to clear abnormally phosphorylated tau, preserving a pool of toxic tau intermediates within the neuron. We describe a mechanism for tau clearance involving a major cellular kinase, Akt. During stress, Akt is ubiquitinated and degraded by the tau ubiquitin ligase CHIP, and this largely depends on the Hsp90 complex. Akt also prevents CHIP-induced tau ubiquitination and its subsequent degradation, either by regulating the Hsp90/CHIP complex directly or by competing as a client protein with tau for binding. Akt levels tightly regulate the expression of CHIP, such that, as Akt levels are suppressed, CHIP levels also decrease, suggesting a potential stress response feedback mechanism between ligase and kinase activity. We also show that Akt and the microtubule affinity-regulating kinase 2 (PAR1/MARK2), a known tau kinase, interact directly. Akt enhances the activity of PAR1 to promote tau hyperphosphorylation at S262/S356, a tau species that is not recognized by the CHIP/Hsp90 complex. Moreover, Akt1 knockout mice have reduced levels of tau phosphorylated at PAR1/MARK2 consensus sites. Hence, Akt serves as a major regulator of tau biology by manipulating both tau kinases and protein quality control, providing a link to several common pathways that have demonstrated dysfunction in Alzheimer's disease.