Clock-drawing potentially mediates the effect of depression on mortality: replication in three cohorts

OBJECTIVE: Previously studies have associated visuospatial tasks, particularly 'clock-drawing', with mortality. We sought to determine whether clock-drawing also mediates the association between depressive symptoms and mortality. PARTICIPANTS: Non-institutionalized Hispanic and non-Hispanic White elderly volunteers. MEASUREMENTS: Survival curves were generated as a function of baseline depressive symptom ratings. Significant models were adjusted for CLOX performance. CLOX is divided into CLOX1, a measure of executive control, and CLOX2, a measure of visuospatial skills. DESIGN: Retrospective analysis of three longitudinal cohorts. RESULTS: CLOX2 and depressive symptoms were both associated with mortality in unadjusted models. CLOX2 predicted survival independently of CLOX1 in all three cohorts. CLOX2 also attenuated, and/or mediated the association between depressive symptoms and mortality. These results withstood adjustment for age and education in all three cohorts. CONCLUSION: Regardless of the sample examined, or the measure of depressive symptoms applied, the association between depressive symptoms and mortality appears to be at least partially mediated by visuospatial skills. This finding supports our hypothesis that right hemisphere structural brain disease, particularly that involving the insula, may mediate depression's effects on mortality.     

Lipoprotein(a) concentrations in Mexican Americans and non-Hispanic whites: the San Antonio Heart Study.

There is considerable evidence that lipoprotein(a) (Lp(a)) is a strong independent risk factor for coronary heart disease. Based on their risk factor profile, Mexican Americans have an increased risk of coronary heart disease, yet Mexican Americans have coronary heart disease mortality similar to or lower than that of non-Hispanic whites. The authors therefore attempted to determine whether Mexican Americans had decreased Lp(a) concentrations relative to non-Hispanic whites in the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Lp(a) concentrations (mg/dl) were significantly lower in Mexican Americans (n = 316) than in non-Hispanic whites (n = 242) (men: 10.4 vs. 16.3; women: 11.5 vs. 16.4). In addition, the proportion of persons with Lp(a) concentrations of > or = 30 mg/dl (the threshold at which increased risk of coronary heart disease is believed to occur) was significantly higher in non-Hispanic whites than in Mexican Americans (18.6% vs. 7.6%; Mantel-Haenszel odds ratio (adjusted for sex) = 2.79). Age, obesity, body fat distribution, cigarette smoking, alcohol consumption, and glucose and insulin concentrations were not significantly related to Lp(a) levels. Decreased Lp(a) concentrations may account in part for Mexican Americans' relative protection from coronary heart disease mortality.     

Central adiposity and gallbladder disease in Mexican Americans

Obesity is widely recognized as a risk factor for gallstones. However, to the authors' knowledge, only one study has examined the effect of body fat distribution on the prevalence of gallbladder disease. Mexican Americans are a population characterized by both a high prevalence of gallbladder disease and an unfavorable body fat distribution. The authors examined whether central adiposity (as measured by the ratio of subscapular-to-triceps skinfold) was related to clinically evident gallbladder disease in 1,202 Mexican Americans and 908 non-Hispanic whites in the San Antonio Heart Study from 1979 to 1982. After adjustment for overall adiposity (as measured by body mass index) and the ratio of subscapular-to-triceps skinfold, an increased prevalence of gallbladder disease was still observed in Mexican-American women. Both body mass index and the ratio of subscapular-to-triceps skinfold were positively and independently associated with gallbladder disease in women, while in men, body mass index, but not the subscapular-to-triceps skinfold ratio, was associated with gallbladder disease. Central adiposity is also related to the adverse pattern of cardiovascular risk factors observed in women with gallbladder disease.     

Replication fitness and NS5B drug sensitivity of diverse hepatitis C virus isolates characterized by using a transient replication assay

The innate genetic variability characteristic of chronic hepatitis C virus (HCV) infection makes drug resistance a concern in the clinical development of HCV inhibitors. To address this, a transient replication assay was developed to evaluate the replication fitness and the drug sensitivity of NS5B sequences isolated from the sera of patients with chronic HCV infection. This novel assay directly compares replication between NS5B isolates, thus bypassing the potential sequence and metabolic differences which may arise with independent replicon cell lines. Patient-derived NS5B sequences were similar to those of the established HCV genotypes, but isolates from each patient shared genetic variability specific to that patient, with additional genetic variability observed across the individual isolates. Every sample provided functional NS5B isolates which supported subgenomic replication, frequently to levels comparable to that of laboratory-optimized replicons. All isolates were equivalently sensitive to an active-site nucleoside inhibitor, but the sensitivities to a panel of nonnucleoside inhibitors which targeted three distinct sites on NS5B varied among the isolates. In con1, the original laboratory-optimized replicon, the NS5B S282T substitution confers resistance to the nucleoside inhibitor but impairs replication. This substitution was engineered into both genotype 1a and genotype 1b isolates. Replication was severely debilitated, demonstrating that no compensatory residues were encoded within these genetically diverse sequences to increase the replication fitness of the mutated replicons. This work describes a transient replicon-based assay that can support the clinical development of compounds which target NS5B and demonstrates its utility by examining several patient-derived NS5B isolates for replication fitness and differential sensitivity to NS5B inhibitors.