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.

BackgroundWe evaluated the amounts of amyloid beta (Aβ)) peptides in the central nervous system (CNS) and in reservoirs outside the CNS and their potential impact on Aβ plasma levels and Alzheimer's disease (AD) pathology.MethodsAmyloid β levels were measured in (1) the plasma of AD and nondemented (ND) controls in a longitudinal study, (2) the plasma of a cohort of AD patients receiving a cholinesterase inhibitor, and (3) the skeletal muscle, liver, aorta, platelets, leptomeningeal arteries, and in gray and white matter of AD and ND control subjects.ResultsPlasma Aβ levels fluctuated over time and among individuals, suggesting continuous contributions from brain and peripheral tissues and associations with reactive circulating proteins. Arteries with atherosclerosis had larger amounts of Aβ40 than disease‐free vessels. Inactivated platelets contained more Aβ peptides than activated ones. Substantially more Aβ was present in liver samples from ND patients. Overall, AD brain and skeletal muscle contained increased levels of Aβ.ConclusionsEfforts to use plasma levels of Aβ peptides as AD biomarkers or disease‐staging scales have failed. Peripheral tissues might contribute to both the circulating amyloid pool and AD pathology within the brain and its vasculature. The wide spread of plasma Aβ values is also due in part to the ability of Aβ to bind to a variety of plasma and membrane proteins. Sources outside the CNS must be accounted for because pharmacologic interventions to reduce cerebral amyloid are assessed by monitoring Aβ plasma levels. Furthermore, the long‐range impact of Aβ immunotherapy on peripheral Aβ sources should also be considered.

While researchers have suggested that joint mobility would probably be affected by age and gender, research findings often present discrepancies. Little research has been performed on the factors which effect mobility of the trapeziometacarpal (TMC) joint. The purpose of this study was to address the effects of age and gender on the ranges of motion of the normal TMC joint. Eighty normal subjects divided into four age groups participated in this study. The TMC joint motions were recorded using an electromagnetic tracking system. In order to achieve a maximal range of TMC joint motion which was defined as the maximal workspace, each subject was asked to perform actively maximal circumduction, flexion—extension, and abduction—adduction of the TMC joint. Numerical and statistical methods were used to compute the TMC workspace and to detect significant differences. A workspace-to-length ratio was determined as an index to examine the effects of the age and gender on the joint mobility. The results demonstrated that age and gender had significant influences on the TMC workspace among the groups studied. The understanding of TMC joint mobility under different age and gender conditions is achieved through this study. The findings can be used to report clinical measures in the determination of the extent of impairment of osteoarthritis as well as the outcomes between pre- and post-surgical (or non-surgical) interventions.

Abstract Barrett's esophagus, a columnar metaplasia of the lower esophagus epithelium related to gastroesophageal reflux disease, is the strongest known risk factor for the development of esophageal adenocarcinoma (EAC). Understanding the signal transduction events involved in esophageal epithelium carcinogenesis may provide insights into the origins of EAC and may suggest new therapies. To elucidate the molecular pathways of bile acid–induced tumorigenesis, the newly identified inflammation-associated signaling pathway involving IκB kinases β (IKKβ), tuberous sclerosis complex 1 (TSC1), and mammalian target of rapamycin (mTOR) downstream effector S6 kinase (S6K1) was confirmed to be activated in immortalized Barrett's CPC-A and CPC-C cells and esophageal cancer SEG-1 and BE3 cells. Phosphorylation of TSC1 and S6K1 was induced in response to bile acid stimulation. Treatment of these cells with the mTOR inhibitor rapamycin or the IKKβ inhibitor Bay 11-7082 suppressed bile acid–induced cell proliferation and anchorage-independent growth. We next used an orthotopic rat model to evaluate the role of bile acid in the progression of Barrett's esophagus to EAC. Of interest, we found high expression of phosphorylated IKKβ (pIKKβ) and phosphorylated S6K1 (pS6K1) in tumor tissues and the Barrett's epithelium compared with normal epithelium. Furthermore, immunostaining of clinical EAC tissue specimens revealed that pIKKβ expression was strongly correlated with pS6K1 level. Together, these results show that bile acid can deregulate TSC1/mTOR through IKKβ signaling, which may play a critical role in EAC progression. In addition, Bay 11-7082 and rapamycin may potentially be chemopreventive drugs against Barrett's esophagus–associated EAC. [Cancer Res 2008;68(8):2632–40]

The specific aim of this study was to develop a quantitative method and a kinematic method to evaluate the maximal workspace of the trapeziometacarpal (TM) joint. Six fresh-frozen human cadaver hands were disarticulated 4 cm proximal to the wrist joint and used in this experiment. The three-dimensional motion data of the TM joint was collected by an electromagnetic tracking device at 30 Hz. The workspace was reconstructed according to a complete set of motion data included circumduction, flexion-extension and abduction-adduction. A spherical fitting technique was used to obtain a sphere encompassing all the motion trajectories and estimating the centre of the sphere. The surface area of the maximal TM workspace, located on the one part of the sphere surface, was calculated by surface integration. The interclass correlation coefficient values for the reliability estimation of the repeated measurements of the radius and surface area of all specimens were 0.91 and 0.98 respectively. The mean coefficients of variance of the measured radius and the surface area were 2.04 per cent and 3.65 per cent respectively. The results also showed that using a spherical model to calculate the maximal workspace as an index for assessing TM joint impairment is practical.