Association of monocyte tumor necrosis factor α expression and serum inflammatory biomarkers with walking impairment in peripheral artery disease.

OBJECTIVE: Inflammation contributes to the development of peripheral artery disease (PAD) and may contribute to intermittent claudication by adversely affecting vascular and skeletal muscle function. We explored the association of inflammation to maximal walking time (MWT) in patients with claudication. METHODS: Circulating inflammatory biomarkers, including tumor necrosis factor α (TNF-α), C-reactive protein (CRP), interleukin-6 (IL-6), and soluble intercellular adhesion molecule 1 (sICAM), were measured in 75 subjects with intermittent claudication as well as in 43 healthy subjects. Real-time polymerase chain reaction was used to quantify mRNA expression of TNF-α, IL-6, interferon-γ, and CD36 from peripheral blood monocytes. Treadmill testing was performed in PAD subjects to assess MWT. RESULTS: Compared with healthy subjects, PAD subjects had higher levels of circulating TNF-α (P < .0001), CRP (P = .003), sICAM (P < .0001), and IL-6 (P < .0001). Expression of both IL-6 (P = .024) and CD36 (P = .018) was greater in PAD subjects than in healthy subjects. Among subjects with PAD, higher gene expression of TNF-α was associated inversely with MWT (P = .01). MWT was also associated inversely with greater levels of circulating TNF-α (P = .028), CRP (P = .024), IL-6 (P = .03), and sICAM (P = .018). CONCLUSIONS: Systemic inflammation, as indicated by TNF-α inflammatory gene expression in peripheral blood monocytes and by circulating biomarker levels, is associated with impairment in walking time in patients with PAD and intermittent claudication.

Picture superiority doubly dissociates the ERP correlates of recollection and familiarity.

Two experiments investigated the processes underlying the picture superiority effect on recognition memory. Studied pictures were associated with higher accuracy than studied words, regardless of whether test stimuli were words (Experiment 1) or pictures (Experiment 2). Event-related brain potentials (ERPs) recorded during test suggested that the 300-500 msec FN400 old/new effect, hypothesized to be related to familiarity-based recognition, benefited from study/test congruity, such that it was larger when study and test format remained constant than when they differed. The 500-800 msec parietal old/new effect, hypothesized to be related to recollection, benefited from studying pictures, regardless of test format. The parallel between the accuracy and parietal ERP results suggests that picture superiority may arise from encoding the distinctive attributes of pictures in a manner that enhances their later recollection. Furthermore, when words were tested, opposite effects of studying words versus studying pictures were observed on the FN400 (word > picture) versus parietal (picture > word) old/new effects--providing strong evidence for a crossover interaction between these components that is consistent with a dual-process perspective.

Impaired skeletal muscle glucose uptake by [18F]fluorodeoxyglucose-positron emission tomography in patients with peripheral artery disease and intermittent claudication.

OBJECTIVE: Reduced limb perfusion from arterial stenosis does not adequately account for intermittent claudication symptoms in peripheral artery disease (PAD). Insulin resistance is associated with PAD and may contribute to claudication by impairing skeletal muscle metabolism. We aimed to determine whether skeletal muscle glucose uptake, assessed by [(18)F]fluorodeoxyglucose positron emission tomography, is reduced in patients with claudication. METHODS AND RESULTS: Thirty-seven subjects with PAD and claudication and 11 healthy controls underwent [(18)F]fluorodeoxyglucose-positron emission tomography imaging of the legs during hyperinsulinemic-euglycemic clamp. Calf glucose uptake was quantified by graphical Patlak analysis, and whole-body insulin sensitivity was assessed as the glucose disposal rate (M) from the insulin clamp. Compared with healthy controls, PAD subjects were insulin resistant (M=3.4 mg/kg per minute [interquartile range, 2.7 to 4.8] versus 5.0 [3.7 to 6.6], P=0.019). Calf muscle glucose uptake was significantly lower in PAD compared with healthy subjects (48.6±2.6 µmol/kg per minute versus 62.9±6.5 µmol/kg per minute, P=0.009) and correlated with systemic insulin sensitivity (r=0.37, P=0.03) in PAD subjects. These abnormalities persisted even after exclusion of PAD subjects with diabetes. CONCLUSIONS: Patients with claudication have impaired calf muscle glucose uptake. Future studies are required to assess whether calf muscle insulin resistance contributes to exercise limitation in patients with intermittent claudication.

Green tea epigallocatechin 3-gallate accumulates in mitochondria and displays a selective antiapoptotic effect against inducers of mitochondrial oxidative stress in neurons.

Epigallocatechin-3-gallate (EGCG) is a major flavonoid component of green tea that displays antiapoptotic effects in numerous models of neurotoxicity. Although the intrinsic free radical scavenging activity of EGCG likely contributes to its antiapoptotic effect, other modes of action have also been suggested. We systematically analyzed the antiapoptotic action of EGCG in primary cultures of rat cerebellar granule neurons (CGNs). The dose-dependent protective effects of EGCG were determined after coincubation with eight different stimuli that each induced neuronal apoptosis by distinct mechanisms. Under these conditions, EGCG provided significant neuroprotection only from insults that induce apoptosis by causing mitochondrial oxidative stress. Despite this selective antiapoptotic effect, EGCG did not significantly alter the endogenous activities or expression of Mn(2+)- superoxide dismutase, glutathione peroxidase, Nrf2, or Bcl-2. Subfractionation of CGNs after incubation with (3)H-EGCG revealed that a striking 90-95% of the polyphenol accumulated in the mitochondrial fraction. These data demonstrate that EGCG selectively protects neurons from apoptosis induced by mitochondrial oxidative stress. This effect is likely due to accumulation of EGCG in the mitochondria, where it acts locally as a free radical scavenger. These properties of EGCG make it an interesting therapeutic candidate for neurodegenerative diseases involving neuronal apoptosis triggered by mitochondrial oxidative stress.

Pharmacotherapy and behavioral intervention for peripheral arterial disease.

Lower-extremity peripheral arterial disease is a chronic disease process resulting from atherosclerotic obstruction of major vessels supplying the legs. A significant manifestation of systemic atherosclerosis, it is estimated to affect more than 10 million adults in the United States alone. The reported incidence is a conservative estimate, because many patients who suffer from symptoms of peripheral arterial disease attribute them to "normal aging" and may not report them to their physician. Additionally, physicians may miss the diagnosis if a comprehensive history and vascular examination are not a routine part of their assessment. The hallmark symptom of peripheral arterial disease is intermittent claudication, defined as reproducible muscular leg pain that is precipitated by exercise and relieved by rest. Intermittent claudication not only limits functional capacity and adversely affects quality of life but is also an ominous predictor of increased risk for myocardial infarction, stroke, and cardiovascular death. Due to the chronicity of atherosclerosis, medical intervention is most successful when a comprehensive team approach is utilized, involving the patient, family, and vascular health professionals. Treatment for peripheral arterial disease is aimed at first, minimizing symptoms and disease progression via smoking cessation, supervised exercise therapy, pharmacotherapy, and/or revascularization, and second, minimizing the risk of cardiovascular mortality via risk factor identification and reduction, and the use of antiplatelet therapy.