Atrial fibrillation, hypertension, and angina were associated with a greater rate of decline and may represent modifiable risk factors for secondary prevention in Alzheimer disease. The attenuated decline for diabetes and coronary artery bypass graft surgery may be due to selective survival. Some of these effects appear to vary with age.

Higher levels of accordance with both the DASH and Mediterranean dietary patterns were associated with consistently higher levels of cognitive function in elderly men and women over an 11-y period. Whole grains and nuts and legumes were positively associated with higher cognitive functions and may be core neuroprotective foods common to various healthy plant-centered diets around the globe.

Neuropsychiatric symptoms in dementia overall were highly persistent. Among those in whom symptoms did persist, symptom severity a year and a half later appeared to be comparable.

The role of antioxidant intake in osteoporotic hip fracture risk is uncertain and may be modified by smoking. In the Utah Study of Nutrition and Bone Health, a statewide, population-based case-control study, the authors investigated whether antioxidant intake was associated with risk of osteoporotic hip fracture and whether this association was modified by smoking status. The analyses included data on 1,215 male and female cases aged > or = 50 years who incurred a hip fracture during 1997-2001 and 1,349 age- and sex-matched controls. Diet was assessed by food frequency questionnaire. Among ever smokers, participants in the highest quintile of vitamin E intake (vs. the lowest) had a lower risk of hip fracture after adjustment for confounders (odds ratio = 0.29, 95% confidence interval (CI): 0.16, 0.52; p-trend < 0.0001). The corresponding odds ratio for beta-carotene intake was 0.39 (95% CI: 0.23, 0.68; p-trend = 0.0004), and for selenium intake it was 0.27 (95% CI: 0.12, 0.58; p-trend = 0.0003). Vitamin C intake did not have a significant graded association with hip fracture risk among ever smokers. Similar findings were obtained when an overall antioxidant intake score was used (odds ratio = 0.19, 95% CI: 0.10, 0.37; p-trend < 0.0001). No similar associations were found in never smokers. Antioxidant intake was associated with reduced risk of osteoporotic hip fracture in these elderly subjects, and the effect was strongly modified by smoking status.

Aggrecanases are now believed to be the principal proteinases responsible for aggrecan degradation in osteoarthritis. Given their potential as a drug target, we solved crystal structures of the two most active human aggrecanase isoforms, ADAMTS4 and ADAMTS5, each in complex with bound inhibitor and one wherein the enzyme is in apo form. These structures show that the unliganded and inhibitor-bound enzymes exhibit two essentially different catalytic-site configurations: an autoinhibited, nonbinding, closed form and an open, binding form. On this basis, we propose that mature aggrecanases exist as an ensemble of at least two isomers, only one of which is proteolytically active.Keywords: protein structure; enzymes; metalloproteins; aggrecanases Supplemental material: see www.proteinscience.org Osteoarthritis (OA) is a progressive disease that results in degradation of articular cartilage and chronic pain. The extracellular matrix is composed of two major components, aggrecan and collagen. Aggrecan is a large multidomain proteoglycan that provides cartilage with compressibility and elasticity by swelling and hydrating the collagen network (Vertel and Ratcliffe 2000). Loss of aggrecan is considered a critical early event in OA, occurring initially at the joint surface and progressing to the deeper zones. This is followed by degradation of collagen fibrils and mechanical failure of the tissue (Nagase and Kashiwagi 2003). Aggrecanase-1 (ADAMTS4) and aggrecanase-2 (ADAMTS5), members of the ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) gene family, cleave aggrecan at a unique site termed the ''aggrecanase site Tortorella et al. 1999). ADAMTS4 and ADAMTS5 are expressed in human normal and OA cartilage (Yamanishi et al. 2002) and in OA synovium, and contribute to the structural damage that characterizes human OA (Powell et al. 2007;Song et al. 2007). However, there is no consensus in the literature as to which aggrecanase is the most important in human OA. In mice, ADAMTS5 (but not ADAMTS4) is responsible for disease progression in a surgically induced model of OA (Glasson et al. 2004(Glasson et al. , 2005. ADAMTS4/ADAMTS5 double knockout mice are physiologically normal (Majumdar et al. 2007) and also protected from developing OA. Given the normal phenotype of the double knockout mice, dual inhibition Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi