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To determine the association between performance on selected tasks of everyday life and impairment in visual acuity and contrast sensitivity. Methods: Visual acuity and contrast sensitivity were obtained on a population-based sample of 2520 older African American and white subjects. Performance was assessed on mobility, daily activities with a strong visual component, and visually intensive tasks. Disability was defined as performance less than 1 SD below the mean. Receiver operating characteristic curve analyses were used to evaluate the sensitivity and specificity of thresholds in acuity and contrast loss for determining disability. Results: Both visual acuity and contrast sensitivity loss were associated with decrements in function. The relationship of function to the vision measures was mostly linear, therefore, receiver operating characteristic curves were not helpful in identifying cutoff points for predicting disabilities. For mobility tasks, most persons were not disabled until they had significant acuity loss (logMAR visual acuity Ͼ1.0 or Ͻ20/200) or contrast sensitivity loss (0.9 log units contrast sensitivity). For heavily visually intensive tasks, like reading, visual acuity worse than 0.2 logMAR (20/30) or contrast sensitivity worse than 1.4 log units was disabling. Conclusions: Both contrast sensitivity and visual acuity loss contribute independently to deficits in performance on everyday tasks. Defining disability as deficits in performance relative to a population, it is possible to identify visual acuity and contrast loss where most are disabled. However, the cutoff points depend on the task, suggesting that defining disability using a single threshold for visual acuity or contrast sensitivity loss is arbitrary.

Background An unbiased systems approach was utilized to define energy metabolic events that occur during the pathologic cardiac remodeling en route to heart failure. Methods and Results Combined myocardial transcriptomic and metabolomic profiling were conducted in a well-defined mouse model of heart failure that allows comparative assessment of compensated and decompensated (heart failure) forms of cardiac hypertrophy due to pressure overload. The pressure overload datasets were also compared with the myocardial transcriptome and metabolome for an adaptive (physiological) form of cardiac hypertrophy due to endurance exercise training. Comparative analysis of the datasets led to the following conclusions: 1) expression of most genes involved in mitochondrial energy transduction were not significantly changed in the hypertrophied or failing heart, with the notable exception of a progressive downregulation of transcripts encoding proteins and enzymes involved in myocyte fatty acid transport and oxidation during the development of heart failure; 2) tissue metabolite profiles were more broadly regulated than corresponding metabolic gene regulatory changes, suggesting significant regulation at the post-transcriptional level; 3) metabolomic signatures distinguished pathologic and physiological forms of cardiac hypertrophy and served as robust markers for the onset of heart failure; and 4) the pattern of metabolite derangements in the failing heart suggests “bottlenecks” of carbon substrate flux into the Krebs cycle. Conclusions Mitochondrial energy metabolic derangements that occur during the early development of pressure overload-induced heart failure involve both transcriptional and post-transcriptional events. A subset of the myocardial metabolomic profile robustly distinguished pathologic and physiologic cardiac remodeling.

SUMMARY Red blood cell production is a finely tuned process that requires coordinated oxygen- and iron-dependent regulation of cell differentiation and iron metabolism. Here we show that translational regulation of HIF-2α synthesis by IRP1 is critical for controlling erythrocyte number. IRP1 null mice (Irp1−/−) display a marked transient polycythemia. HIF-2α mRNA is derepressed in kidney of Irp1−/− but not Irp2−/− mice leading to increased renal erythropoietin (Epo) mRNA and inappropriately elevated serum Epo levels. Expression of the iron transport genes DCytb, DMT1 and ferroportin as well as other HIF-2α targets is enhanced in IRP1−/− duodenum. Analysis of mRNA translation state in liver revealed IRP1-dependent dysregulation of HIF-2α mRNA translation while IRP2 deficiency derepressed translation of all other known 5′ IRE-containing mRNAs expressed in liver. These results uncover separable physiological roles of each IRP and identify IRP1 as a therapeutic target for manipulating HIF-2α action in hematologic, oncologic and other disorders.